ABCMdb

ABCC7 p.Ala455Glu

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II-III (maturation defect, gating defect) <a href="https://www.ncbi.nlm.nih.gov/pubmed/26823392">Veit et al.</a>
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Publications

PMID: 16442101 [PubMed] Frelet A et al: "Insight in eukaryotic ABC transporter function by mutation analysis."

No. Sentence Comment

307 [138] A455E, P574H cAMP-stimulated apical membrane Cl-currents but current magnitudes were reduced compared to wild-type Electrophysiology of epithelial cells [139] C491S, C1344S, C1355S C491S channels opened almost exclusively to a 3-pS subconductance. Login to comment

PMID: 10021451 [PubMed] Zeitlin PL et al: "Novel pharmacologic therapies for cystic fibrosis."

No. Sentence Comment

33 Examples of Class V mutations include 3849 + 10kb C→T, A455E, and 5T. Login to comment
133 Class IV mutations such as R117H, R334W, R347P, A455E, and P574H are associated with a pancreatic sufficient phenotype or late onset pancreatic insufficiency. Login to comment

PMID: 10099982 [PubMed] Dohle GR et al: "The complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data."

No. Sentence Comment

58 CFTR mutation analysis was performed for 10 mutations: we analysed for the mutations R117H, A455E, ∆F508, 1717-1G→A, G542X, R553X, R1162X, S1251N, W1282X, and N1303K. Login to comment
81 Chymotr.Ͻ 23/22 CF response (I) ∆F508/R117H 9/7 CF in family 3 33 CARA/oily stools GgtϾ,Chymotr.Ͻ 23/36 CF response (I) ∆F508/- 9/7 4 31 Pelvic re kidney NA 10/22 CF response (I) -/- 7/7 5 32 Sinusitis/nasal Chymotr.Ͻ 50/52 CF low residual (II) A455E/- 9/5 Partner ∆dF508 polyps 6 38 NA NA 40/43 CF high residual (III) A445E/R117H 9/7 7 27 NA GgtϾ,Chymotr.Ͻ 28/44 CF high residual (III) R117H/R553X 7/7 Partner R117H 8 38 Nasal polyps NA 34/51 CF high residual (III) ∆F508/R117H 9/7 Pertussis 9 36 NA NA 58/70 CF high residual (III) ∆F508/- 9/5 10 31 NA GgtϾ 54/70 CF high residual (III) ∆F508/- 9/5 Partner R117H 11 32 Maldescended GgtϾ 16/34 CF high residual (III) -/- 9/7 Single kidney in family testis 12 35 NA NA 14/21 Inconclusive ∆F508/- 9/7 13 29 NA NA 43/70 Normal response (IV) A455E/R117H 9/7 14 38 NA NA 32/55 Normal response (IV) R117H/1717-1→G→A 7/7 15 29 NA GgtϾ 44/66 Normal response (IV) ∆F508/R117H 9/7 16 28 NA NA 42/48 Normal response (IV) R117H/- 7/7 17 36 NA NA 22/44 Normal response (IV) -/- 7/5 Non-Caucasian 18 34 NA NA 57/30 Normal response (IV) -/- 7/7 Non-Caucasian 19 39 NA NA 36/52 Normal response (IV) -/- 7/7 Non-Caucasian 20 31 NA NA 16/30 Normal response (IV) -/- 7/7 Non-Caucasian 21 34 NA NA 20/41 Normal response (IV) -/- 7/7 NA ϭ no abnormalities, GgT ϭ gamma glutamyl transpeptidase, Chymotr. Login to comment

PMID: 10325907 [PubMed] Bronsveld I et al: "Clinical presentation of exclusive cystic fibrosis lung disease."

No. Sentence Comment

68 Other cases of CF with normal sweat test results and pulmonary disease, as described for patients carrying the A455E or 3849+10 kb C->T mutation,7 8 22 23 can clearly be diagnosed by an abnormal ICM even when there are few or no clinical signs of gastrointestinal involvement.10 The CFTR gene was screened for disease causing lesions in all exons and flanking intron sequences and on one chromosome a sequence alteration in a donor splice site was found Figure 2 Nasal potential diVerence (PD) measurements of the patient (x) and mean (SD) PD values of 25 controls (L) and 23 patients with CF ( ) following superfusion with saline solution, amiloride (10-4 M) in saline solution, Cl-free solution with amiloride, isoprenaline (10-4 M) in Cl-free solution with amiloride, and ATP (10-3 M) in Cl-free solution with amiloride and isoprenaline. Login to comment

PMID: 10362539 [PubMed] Ostedgaard LS et al: "Processing of CFTR bearing the P574H mutation differs from wild-type and deltaF508-CFTR."

No. Sentence Comment

18 Earlier studies showed that the CF-associated mutants, P574H and A455E, were also misprocessed. Login to comment
19 In this study, we found that processing of P574H and A455E was also temperature-sensitive; at 26°C, some of the protein matured. Login to comment
27 We earlier studied two other CF-associated mutations located in NBD1, A455E and P574H (Sheppard et al., 1995). Login to comment
29 However, A455E and P574H generate reduced net epithelial current because the proteins are misprocessed and few functional channels reach the plasma membrane (Sheppard et al., 1995; Champigny et al., 1995). Login to comment
30 Nevertheless, the processing defect of A455E and P574H is less pronounced than that of ∆F508 and the resulting clinical phenotype is less severe (Kristidis et al., 1992; Kerem et al., 1990a; Veeze et al., 1994; Gan et al., 1995). Login to comment
32 In this study, we compared the processing of P574H and A455E mutants to that of ∆F508. Login to comment
37 Using the pcDNA3-6His-CFTR as a backbone, we made the constructs A455E, P574H and ∆F508 (Kunkel, 1985) and confirmed the mutations by DNA sequencing in both directions. Login to comment
65 RESULTS Because earlier studies suggested that lowering the temperature allowed ∆F508 to fold correctly and exit the ER (Denning et al., 1992a; Lukacs et al., 1993; Sato et al., 1996), we first examined the temperature-sensitivity of A455E and P574H processing. Login to comment
70 For the NBD1 mutants, ∆F508 (B), A455E (C) and P574H (D), band B was the primary form detected at 37°C. Login to comment
74 For ∆F508 (B) and A455E (C), the relative amount of band C was minimal at each time at 37°C. Although the relative amount of band C in P574H (D) was also low, it increased slowly with time at 37°C. Login to comment
75 When the temperature was reduced to 26°C, the relative amount of band C for ∆F508 and A455E increased modestly, while the amount of P574H band C relative to total P574H increased. Login to comment
77 These results indicate that, like ∆F508, both A455E and P574H are temperature-sensitive processing mutants. Login to comment
78 Moreover, P574H makes relatively more band C at both 37°C and 26°C than either ∆F508 or A455E. Login to comment
82 P574H and A455E are temperature-sensitive mutants. Login to comment
83 COS-7 cells were electroporated with pcDNA3 vectors encoding wild-type CFTR (A), ∆F508 (B), A455E (C), and P574H (D). Login to comment
111 We used immunocytochemistry to determine if the cellular distribution of ∆F508, A455E and P574H was consistent with the quantitative biochemical differences we had observed. Login to comment
114 The fluorescence pattern of ∆F508 (C) and A455E (E) at 37°C resembles the reticular pattern characteristic of ER with an absence of plasma membrane staining. Login to comment
115 When the cells were incubated at 26°C, cytoplasmic staining became more diffuse and the outline of the cell membrane was occasionally detectable in ∆F508 (D) and A455E (F). Login to comment
118 Immunofluorescence in COS-7 cells electroporated with wild-type-CFTR (A,B); ∆F508 (C,D); A455E (E,F); and P574H (G,H). Login to comment
165 DISCUSSION Earlier work showed that CFTR containing the CF-associated mutations ∆F508, A455E, or P574H decreases cell membrane Cl- current primarily because the mutant proteins fail to fold correctly and therefore do not traffic out of the ER (Cheng et al., 1990; Lukacs et al., 1994; Ward and Kopito, 1994; Sheppard et al., 1995; Qu and Thomas, 1996; Qu et al., 1997; Yang et al., 1993; Zhang et al., 1998). Login to comment
185 We found that, like ∆F508, the processing of P574H and A455E is temperature-sensitive. Login to comment
186 Moreover, unlike ∆F508 and A455E, P574H formed some mature protein at 37°C, and at 26°C, P574H generated relatively more mature protein than ∆F508. Login to comment
189 This is consistent with the clinical phenotype in CF patients: P574H and A455E are associated with a milder, pancreatic-sufficient phenotype and ∆F508 is associated with a severe, pancreatic-insufficient clinical phenotype (Kerem et al., 1990a,b; Kristidis et al., 1992; Veeze et al., 1994; Gan et al., 1995). Login to comment
197 These inclusions were not present in wild-type, ∆F508, A455E or any other mutant we have studied. Login to comment

PMID: 10376575 [PubMed] Mak V et al: "Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia."

No. Sentence Comment

28 Analysis for 31 of the most common CFTR mutations found within the white CF population,60 consisting of ⌬F508, W1282X, G542X, G551D, N1303K, R553X, G85E, R117H, S549N, V520F, R334W, A455E, R347P, R1162X, Y122X, S549R, 621+1G→T, ⌬I507, R560T, R347H, 3659delC, Q493X, 1898+1G→T, 711+1G→T, 3849+10C→T, 1717-1G→A, 3849+4A→G, 3905insT, 1078delT, 2183AA→G, and 2789+5G→A. Briefly, the technique involved amplification by polymerase chain reaction61 of the relevant exons, followed by digestion with appropriate restriction endonucleases and acrylamide gel electrophoresis with ethidium bromide staining. Login to comment

PMID: 10439967 [PubMed] Liechti-Gallati S et al: "Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease."

No. Sentence Comment

20 The distribution of analysed known mutations is similar to that of the total number of mutations in the entire CFTR gene: missense mutations account for 35% (G27E, G85E, R117H, A120T, I148T, H199Y, R334W, T338I, R347P, R347H, A455E, M718K, S5449N, S5449I, G551D, R560T, R560S, S945L, S977P, I1005R, R1066C, R1070Q, M1101K, D1152H, S1235R, R1283M, N1303K, N1303H), followed by 28% of frameshift mutations (175delC, 394delTT, 457TAT- > G, 905delG, 1078delT, I507, F508, 1609delCA, 1677delTA, 2143delT, 2176insC, 218delA, 2184insA, 2869insG, 3659delC, 3732delA, 3821delT, 3905insT, 4016insT, 4172delGC, 4382delA), 21% of nonsense mutations (Q30X, Q39X, Q220X, W401X, Q525X, G542X, Q552X, R553X, V569X, E585X, K710X, R792X, Y1092X, R1162X, S1255X, W1282X, E1371X), and 16% of splice site mutations (621 + 1G- > T, 711 + 1G- > T, 711 + 5G- > A, 1717-1G- > A, 1898 + 1G- > A, 1898 + 5G- > T, 2789 + 5G- > A, 3271 + 1G- > A, 3272-26A- > G, 3601-17T- > C, 3849 + 4A- > G, 3849 + 10kbC- > T, 4374 + 1G- > T). Login to comment
34 Intron 19, all 27 exons and their exon-intron boundaries, including the 24 most common mutations worldwide (G85E, R117H, 621 + 1G- > T, 711 + 1G- > T, 1078delT, R334W, R347P, A455E, I507, F508, 1717-1G- > A, G542X, S549N, G551D, R553X, R560T, 1898 + 1G- > A, 2184delA, 2789 + 5G- > A, R1162X, 3659delC, 3849 + 10kbC- > T, W1282X, N1303K) (Cystic Fibrosis Genetic Analysis Consortium 1994), and the 15 most common mutations in our population (I148T, 1078delT, R334W, R347P, F508, 1717-1G- > A, G542X, R553X, 2347delG, D1152H, R1162X, 3849 + 10kbC- > T, 3905insT, W1282X, N1303K), were considered in this study. Login to comment

PMID: 10444722 [PubMed] Gasparini P et al: "Analysis of 31 CFTR mutations by polymerase chain reaction/oligonucleotide ligation assay in a pilot screening of 4476 newborns for cystic fibrosis."

No. Sentence Comment

46 Table 1 Mutations analysed in the CFTR gene using polymerase chain reaction/oligonucleotide litigation assay/sequence coded separation Mutation Location Nucleotide Result F508 Exon 10 3 bp deletion Deletion of Phe-508 I507 Exon 10 3 bp deletion Deletion of Ile-507 (or -506) Q493X Exon 10 C-1609 →→ T Gln-493 → Stop V520F Exon 10 G-1690 → T Val-520 → Phe 1717-1G → A Intron 10 G-1717-1 → A 3`-splice site mutation G542X Exon 11 G-1756 → T Gly-542 → Stop G551D Exon 11 G-1784 → A Gly-551 → Asp R553X Exon 11 C-1789 → T Arg-553 → Stop R560T Exon 11 G-1811 → C Arg-560 → Thr S549R Exon 11 T-1779 → G Ser-549 → Arg S549N Exon 11 G-1778 → A Ser-549 → Asn 3849+10 kb C → T Intron 19 C-3849+10 kb → T Splice mutation 3849+4A → G Intron 19 A-3849+4 → G Splice mutation R1162X Exon 19 C-3616 → T Arg-1162 → Stop 3659delC Exon 19 1 bp deletion Frameshift W1282X Exon 20 G-3978 → A Trp-1282 → Stop 3905insT Exon 20 1 bp insertion Frameshift N1303K Exon 21 C-4041 → G Asn-1303 → Lys G85E Exon 3 G-386 → A Gly-85 → Glu 621+1G → T Intron 4 G-621+1 → T 5`-splice site mutation R117H Exon 4 G-482 → A Arg-117 → His Y122X Exon 4 T-498 → A Tyr-122 → Stop 711+1G → T Intron 5 G-711+1 → T 5`-splice site mutation 1078delT Exon 7 1 bp deletion Frameshift R347P Exon 7 G-1172 → C Arg-347 → Pro R347H Exon 7 G-1172 → A Arg-347 → His R334W Exon 7 C-1132 → T Arg-334 → Trp A455E Exon 9 C-1496 → A Ala-455 → Glu 1898+1G → A Intron 12 G-1898+1 → A 5`-splice site mutation 2184delA Exon 13 Deletion A-2184; A-2183 → G Frameshift 2789+5G → A Intron 14B G-2789+5 → A Splice mutation Table 2 Summary of cystic fibrosis screening results No of samples analysed Normal subjects Carriers Carrier frequency Turin 1574 1521 53 1/29.7 Pavia 1341 1299 42 1/31.9 San Giovanni Rotondo 1561 1512 49 1/31.8 Total 4476 4332 144 1/31.1 Table 3 Detailed list of mutations detected in the Italian population Centre F508 G542X R347P 2183-AG N1303K 711+1GT 1717-1A R347H R117H 1898+1G 2789+5G W1282X R1162X I507 Other TO 33 2 1 1 5 1 1 2 3 2 2 - - - PV 27 - - 1 2 - 1 - 5 - 1 2 1 1 SGR 30 14 2 1 1 1 - - - - - - - - TO, Dipartimento di Patologia Clinica, Ospedale Infantile "Regina Margherita, Torino; PV, Istituto di Anatomia Patologica, Sezione di Anatomia Patologica, Università di Pavia, Pavia; SGR, Servizio di Genetica Medica and Divisione di Neonatologia, IRCCS Casa Sollievo della SoVerenza, San Giovanni Rotondo, Foggia. Login to comment

PMID: 10549060 [PubMed] Reynaud-Gaubert M et al: "[Respiratory disease in cystic fibrosis: from physiopathology to therapy. Kinesitherapy and pulmonary transplantation excluded]."

No. Sentence Comment

70 - Une 5e classe, plus récemment individualisée, cor- respondrait à une insuffisance quantitative de l`expression membranaire de la protéine par ailleurs normale (ex A455E). Login to comment

PMID: 10764788 [PubMed] Van Oene M et al: "Cystic fibrosis mutations lead to carboxyl-terminal fragments that highlight an early biogenesis step of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

1 Analysis of cystic fibrosis-associated missense mutations in the first nucleotide binding domain (NBD1), including A455E, S549R, Y563N, and P574H, revealed reduced levels of mature CFTR with elevated levels of carboxyl-terminal polypeptide fragments of 105 and 90 kDa. Login to comment
41 EXPERIMENTAL PROCEDURES Construction of CFTR Expression Plasmids-The CFTR mutants A455E, S549R, P574H, and Y563N were generated from pBQ6.2 (34) as described previously (35). Login to comment
84 Analysis of the S549R mutant showed measurable but intermediate levels of band C, whereas A455E, Y563N, and P574H mutants showed markedly reduced levels using both tagged and untagged CFTR. Login to comment
88 Predominant levels of CHA-CFTRwt appear at the cell surface, in contrast to CHA-⌬F508 and CHA-A455E, as described in alternate reports with untagged versions (18, 44). Login to comment
92 Identification of Carboxyl CFTR Derivatives-In addition to full-length CFTR forms, both the M3A7 and the anti-HA antibodies revealed products with relative molecular masses of 105 and 90 kDa that were most prominent in detergent extracts of HEK293 cells expressing the A455E and S549R mutants (Fig. 1, B and C, lanes 4 and 5). Login to comment
97 The first involved an analysis of the extract preparation to examine the compartmentalization of CFTR, the second involved analysis of the intermediates at reduced expression levels with the A455E mutant, and the third involved expression in alternate cell types. Login to comment
100 Immunoblot analysis indicated that less than 10% of total immunoreactive band B or carboxyl-terminal polypeptides were present in the original CHA-A455E pellet (Fig. 3A). Login to comment
102 The occurrence of the 90-kDa band, most prominent with the A455E mutant, does suggest that it is relatively less soluble. Login to comment
105 Representative COS-7 cells transfected with (A) CHA-CFTRwt, (B) CHA-⌬F508, (C) CHA-A455E, and (D) CHA-S549R are shown. Login to comment
106 Indirect immunofluorescence revealed a uniform cell surface staining with the monoclonal anti-HA antibody for the wt protein in contrast to the perinuclear staining of the ⌬F508 and A455E mutants. Login to comment
119 1/20 the amount of the CHA-A455E expression plasmid (Fig. 3C). Login to comment
122 Transient transfections were carried out with CHA-tagged CFTRwt, ⌬F508, and A455E in COS-7, CHO-duk- , and CF bronchial epithelium IB3-1 cell lines. Login to comment
123 Immunoblot analysis of detergent extracts indicated that although the levels varied between the cell types, CHA-A455E consistently revealed the most prominent accumulation of the 105-and 90-kDa bands (Fig. 4, A-C). Login to comment
127 The increased sensitivity clearly shows the accumulation of the 105-kDa intermediate in both the wt and A455E extracts. Login to comment
136 In contrast, no mature forms were detected for the A455E mutation (right panel) or with prolonged pulse and/or chase periods (data not shown). Login to comment
137 The 105-and 90-kDa carboxyl-terminal fragments were evident for both CFTRwt and A455E as early as the completion of the pulse (15 min) and rapidly disappeared during the chase. Login to comment
138 These untagged proteins were detectable with a CFTR antibody mixture (M3A7 and L12B4) and were consistently most prominent for the A455E mutant. Login to comment
146 HEK293 cells were transfected with pCMV (vector alone), CHA-A455E, or with mixtures of pCMV and CHA-A455E to maintain constant plasmid-lipid ratios for transfection. Login to comment
155 The half-life of the 105-kDa intermediate of both CFTRwt and A455E was determined to be very similar to that of band B (t1/2 ϳ30-40 min) (16, 17) emphasizing that this fragment is susceptible to proteolysis. Login to comment
161 Epitope-tagged versions of wt and the A455E mutant gave consistent results, as did radioactively labeled and immunoprecipitated untagged CFTR polypeptides (data not shown). Login to comment
172 RIPA soluble CFTR peptides were immunoprecipitated demonstrating that the inhibitors had no effect on the prevalence of the 105-and 90-kDa polypeptides formed during A455E biosynthesis (Fig. 7B). Login to comment
181 It is imposed on the wt protein but is more prominent in the presence of missense mutations such as A455E or S549R. Login to comment
188 The relative levels of the 105-kDa band with CFTRwt, A455E, and ⌬F508 were determined by phosphorimage analysis. Login to comment
196 Further, it is evident that for enhanced proteolytic activity, the mutated amino acid need not be present in the resulting carboxyl fragments as size estimation would preclude this for at least the A455E mutant. Login to comment
209 It would therefore be interesting to closely examine its interaction with the S549R and A455E CFTR mutants. Login to comment
228 The proximity of the amino acid deletion to a proteolytic site may account for this; however, analysis of cells expressing CFTR versions with both the ⌬F508 mutation and either S549R or A455E mutations retain the formation of prominent levels of the carboxyl-terminal fragments (data not shown). Login to comment
237 This is consistent with the findings of the wt protein but less discernible for some mutations such as A455E. Login to comment
238 The A455E, Y563N, and P574H mutations do appear to be able to achieve at least nominal levels of chloride conduction at the cell surface based both on the presenting phenotype in CF patients (54) and on single channel and whole cell current measurements (55) in heterologous expression systems. Login to comment
239 In contrast to the Y563N and P574H mutations, where low levels of mature band C forms were detectable with long exposure and/or long label incorporation times in HEK293 cells (data not shown), fully glycosylated protein could not be detected for A455E using our assay systems. Login to comment
240 Of the NBD1 missense mutations surveyed, A455E degradation products appeared at the highest levels relative to full-length nascent CFTR such that immature band B may be too low to lead to detectable levels of band C. Login to comment

PMID: 10773783 [PubMed] Zielenski J et al: "Genotype and phenotype in cystic fibrosis."

No. Sentence Comment

94 Various mutations may be associated with reduced biosynthesis of fully active CFTR due to partially aberrant splicing (3849+10kbC→T) [25], promoter mutations or inefficient trafficking (A455E) [26, 27]. Login to comment
147 Thus far, the strongest association between mild pulmonary disease and a specific CFTR mutation was found for the missense allele A455E [57, 60, 62]. Login to comment
165 Both studies showed that certain mild alleles (R117H; A455E; 3849+10kbC→T) from class IV or V tend to be associated with significantly lower Cl sweat levels than those for severe alleles ('F508; 621+1G→T; G542X; R553X, etc.). Login to comment

PMID: 10777364 [PubMed] Wang J et al: "A novel mutation in the CFTR gene correlates with severe clinical phenotype in seven Hispanic patients."

No. Sentence Comment

552 The proportion of patients homozygous for F508 remains quite constant between the three age groups, whereas there is a decline in that of the patients carrying the 621+1G→T/ F508 genotype and an increase of those having a F508/A455E or 621+1G→T/A455E genotype. Login to comment
554 The A455E mutation group contains all the patients with that mutation, independently of the second mutation composing their genotype. Login to comment
555 The CF patients carrying the 621+1G→T mutation, but not A455E, were included in a unique group. Login to comment
556 Patients homozygous or compound heterozygous for the F508 mutation, without the 621+1G→T or the A455E mutation, were grouped together. Login to comment
557 We observed an increase of A455E and a depletion of 621+1G→T at older age groups, whereas the frequency of the F508 mutation stayed constant (table 1B). Login to comment
559 The Kaplan-Meier survival analysis could not be performed considering the three mutations because there were no dead patients in the A455E group. Login to comment
564 The F508 and 621+1G→T alleles are known to be severe mutations conferring pancreatic insuYciency when they are combined with another severe mutation.4 8 9 The A455E allele is a mild mutation associated with pancreatic suYciency and exerts a dominant eVect on the severe mutations. Login to comment
565 Compound heterozygotes for the A455E mutation have a milder pulmonary disease, no meconium ileus, and no late complications, such as diabetes and liver cirrhosis.2 Therefore, since pulmonary insuYciency is the major cause of mortality in cystic fibrosis, it is not unexpected that no CF patients carrying the A455E mutation have died unlike the 13% of those with two severe mutations. Login to comment
570 SYLVAIN R RIVARD* CHRISTIAN ALLARD† JEAN-PIERRE LEBLANC† MARCEL MILOT† GERVAIS AUBIN† FERNAND SIMARD† CLAUDE FÉREC‡ MARC DE BRAEKELEER†§¶ *Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Canada Table 1 Distribution of cystic fibrosis patients diagnosed before the age of 5 by age groups in Saguenay-Lac-Saint-Jean, (A) by genotype, (B) by mutation 0-10 years 10.1-20 years Over 20 years All ages No % No % No % No % (A) Genotype F508/ F508 15 (1) 40.5 21 (2) 36.2 18 (3) 42.9 54 (6) 39.4 F508/621+1G→T 12 (1) 32.4 16 (1) 27.6 10 (1*) 23.8 38 (3*) 27.7 F508/A455E 1 2.7 6 10.3 5 11.9 12 8.8 F508/I148T 1 2.7 1 1.7 2 1.5 F508/Y1092X 3 (1) 5.2 1 2.4 4 (1) 2.9 F508/Q890X 1 2.4 1 0.7 F508/R1158X 1 2.4 1 0.7 621+1G→T/621+1G→T 2 (1) 5.4 4 6.9 1 2.4 7 (1) 5.1 621+1G→T/A455E 1 2.7 4 6.9 3 7.1 8 5.8 621+1G→T/711+1G→T 2 (1) 5.4 2 (1) 3.4 4 (2) 2.9 621+1G→T/Y1092X 1 2.7 1 0.7 621+1G→T/S489X 1 2.7 1 0.7 621+1G→T/G85E 1 (1) 1.7 1 (1) 2.4 2 (2) 1.5 A455E/R117C 1 2.7 1 0.7 N1303K/I148T 1 2.4 1 0.7 Total 37 58 42 137 Death (4) 10.8 (6) 10.3 (5*) 11.9 (15*) 10.9 (B) Mutation F508 16 (1) 43.2 25 (3) 43.1 21 (3) 51.2 62 (7) 45.6 621+1G→T 18 (3) 48.6 23 (3) 39.7 12 (2*) 29.3 53 (8*) 39.0 A455E 3 8.1 10 17.2 8 19.5 21 15.4 Total 37 58 41 136 Death (4) 10.8 (6) 10.3 (5*) (12.2) (15*) (11.0) ( ): Number of deaths. Login to comment
573 1 0.8 0.6 0.4 0.2 0 50 Age (y) A455E mutation ∆F508 mutation 621 + 1G T mutation Cumulativesurvival 0 40302010 Letters †Clinique de Fibrose Kystique, Complexe Hospitalier de la Sagamie, Chicoutimi, Canada ‡Établissement de Transfusion Sanguine de Bretagne Occidentale (ETSBO), Brest, France §Institut National d`Etudes Démographiques, Paris, France ¶Laboratoire d`Anthropologie et de Démographie Génétiques, Faculté des Sciences de l`Homme, Université Victor Segalen Bordeaux 2, 3ter Place de la Victoire, F-33076 Bordeaux Cedex, France 1 Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. Login to comment
576 New York: McGraw-Hill, 1989:2649-80. 2 De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment

PMID: 10777368 [PubMed] Rivard SR et al: "Correlation between mutations and age in cystic fibrosis in a French Canadian population."

No. Sentence Comment

552 The proportion of patients homozygous for F508 remains quite constant between the three age groups, whereas there is a decline in that of the patients carrying the 621+1G→T/ F508 genotype and an increase of those having a F508/A455E or 621+1G→T/A455E genotype. Login to comment
554 The A455E mutation group contains all the patients with that mutation, independently of the second mutation composing their genotype. Login to comment
555 The CF patients carrying the 621+1G→T mutation, but not A455E, were included in a unique group. Login to comment
556 Patients homozygous or compound heterozygous for the F508 mutation, without the 621+1G→T or the A455E mutation, were grouped together. Login to comment
557 We observed an increase of A455E and a depletion of 621+1G→T at older age groups, whereas the frequency of the F508 mutation stayed constant (table 1B). Login to comment
559 The Kaplan-Meier survival analysis could not be performed considering the three mutations because there were no dead patients in the A455E group. Login to comment
564 The F508 and 621+1G→T alleles are known to be severe mutations conferring pancreatic insuYciency when they are combined with another severe mutation.4 8 9 The A455E allele is a mild mutation associated with pancreatic suYciency and exerts a dominant eVect on the severe mutations. Login to comment
565 Compound heterozygotes for the A455E mutation have a milder pulmonary disease, no meconium ileus, and no late complications, such as diabetes and liver cirrhosis.2 Therefore, since pulmonary insuYciency is the major cause of mortality in cystic fibrosis, it is not unexpected that no CF patients carrying the A455E mutation have died unlike the 13% of those with two severe mutations. Login to comment
570 SYLVAIN R RIVARD* CHRISTIAN ALLARD† JEAN-PIERRE LEBLANC† MARCEL MILOT† GERVAIS AUBIN† FERNAND SIMARD† CLAUDE FÉREC‡ MARC DE BRAEKELEER†§¶ *Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Canada Table 1 Distribution of cystic fibrosis patients diagnosed before the age of 5 by age groups in Saguenay-Lac-Saint-Jean, (A) by genotype, (B) by mutation 0-10 years 10.1-20 years Over 20 years All ages No % No % No % No % (A) Genotype F508/ F508 15 (1) 40.5 21 (2) 36.2 18 (3) 42.9 54 (6) 39.4 F508/621+1G→T 12 (1) 32.4 16 (1) 27.6 10 (1*) 23.8 38 (3*) 27.7 F508/A455E 1 2.7 6 10.3 5 11.9 12 8.8 F508/I148T 1 2.7 1 1.7 2 1.5 F508/Y1092X 3 (1) 5.2 1 2.4 4 (1) 2.9 F508/Q890X 1 2.4 1 0.7 F508/R1158X 1 2.4 1 0.7 621+1G→T/621+1G→T 2 (1) 5.4 4 6.9 1 2.4 7 (1) 5.1 621+1G→T/A455E 1 2.7 4 6.9 3 7.1 8 5.8 621+1G→T/711+1G→T 2 (1) 5.4 2 (1) 3.4 4 (2) 2.9 621+1G→T/Y1092X 1 2.7 1 0.7 621+1G→T/S489X 1 2.7 1 0.7 621+1G→T/G85E 1 (1) 1.7 1 (1) 2.4 2 (2) 1.5 A455E/R117C 1 2.7 1 0.7 N1303K/I148T 1 2.4 1 0.7 Total 37 58 42 137 Death (4) 10.8 (6) 10.3 (5*) 11.9 (15*) 10.9 (B) Mutation F508 16 (1) 43.2 25 (3) 43.1 21 (3) 51.2 62 (7) 45.6 621+1G→T 18 (3) 48.6 23 (3) 39.7 12 (2*) 29.3 53 (8*) 39.0 A455E 3 8.1 10 17.2 8 19.5 21 15.4 Total 37 58 41 136 Death (4) 10.8 (6) 10.3 (5*) (12.2) (15*) (11.0) ( ): Number of deaths. Login to comment
573 1 0.8 0.6 0.4 0.2 0 50 Age (y) A455E mutation ∆F508 mutation 621 + 1G T mutation Cumulativesurvival 0 40302010 Letters †Clinique de Fibrose Kystique, Complexe Hospitalier de la Sagamie, Chicoutimi, Canada ‡Établissement de Transfusion Sanguine de Bretagne Occidentale (ETSBO), Brest, France §Institut National d`Etudes Démographiques, Paris, France ¶Laboratoire d`Anthropologie et de Démographie Génétiques, Faculté des Sciences de l`Homme, Université Victor Segalen Bordeaux 2, 3ter Place de la Victoire, F-33076 Bordeaux Cedex, France 1 Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. Login to comment
576 New York: McGraw-Hill, 1989:2649-80. 2 De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment

PMID: 10940786 [PubMed] Zeitlin PL et al: "Future pharmacological treatment of cystic fibrosis."

No. Sentence Comment

22 Examples of CFTR mutations organized by classification of the defect in CFTR biosynthesis Type Genotype Phenotype Defect Cell diagram Drugs that may improve phenotype G542X 621+1 G → T 3905insT W1282X R553X 1717-1 G → A PI no CFTR protein no cell surface chloride transport gentamicin G418 Class II [64] 'F508 N1303K (P574H)a (A455E)a PI defective CFTR processing defective CFTR trafficking no cell surface chloride transport chemical chaperones CPX phenylbutyrate deoxyspergualin Class III [64] G551D G551S PI defective chloride channel regulation reduced or absent cell surface chloride transport genistein pyrophosphate Class IV [64, 66] R117H R334W G314E R347P ('F508)a P574H PS reduced chloride conductance reduced levels of cell surface chloride transport genistein milrinone phenylbutyrate Class V [64] 3849+10 kb C → T 2789+5 G → A 3272-26 A → G A455E 3120+1 G → A 1811+1.6 kb A → G 5Tb PS normal CFTR channels reduced numbers of normal CFTR reduced cell surface chloride transport genistein milrinone phenylbutyrate a Some mutants have features of more than one class of defect. Login to comment

PMID: 10950058 [PubMed] Ockenga J et al: "Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis."

No. Sentence Comment

53 Using the ARMS technology (elucigene CF20, Zeneca Diagnostics, Oxfordshire, UK) all samples were tested additionally for the mutations E60X, R347P, A455E, 1078delT, 2183AA3G, G542X, G551D, N1303K, W1282X, 1717-1G3A, R553X, 621ϩ1G3T, R117H, R1162X, 3849ϩ10kbC3T, R334W, S1251N, and 3659delC. Login to comment

PMID: 10973878 [PubMed] Costes B et al: "Prenatal detection by real-time quantitative PCR and characterization of a new CFTR deletion, 3600+15kbdel5.3kb (or CFTRdele19)."

No. Sentence Comment

51 The mutations tested were S549N, S549R, R553X, G551D, V520F, ⌬I507, ⌬F508, Q493X, 1717-1G3A, G542X, R560T, R347P, R347H, 3849ϩ4A3G, W1282X, R334W, 1078delT, 3849ϩ10kbC3T, R1162X, N1303K, 3659delC, 3905insT, A455E, R117H, Y122X, 2183AA3G, 2789ϩ5G3A, 1898ϩ1G3A, 621ϩ1G3T, 711ϩ1G3T, and G85E. Login to comment

PMID: 11025834 [PubMed] Wang X et al: "Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population."

No. Sentence Comment

30 Analysis of CFTR Genes Genomic DNA samples extracted from the blood of participants were screened for 16 mutations (R117H, 621+1G→T, R334W, R347P, A455E, ⌬I507, ⌬F508, 1717-1 G→A, G542X, S549N, G551D, R553X, R560T, 3849+10 Kb C→T, W1282X, and N1303K) that account for 85% of CF alleles in the white population using the multiplex reverse dot hybridization system (Roche Molecular Systems, Alameda, Calif).16,17 This test also identified the 5T, 7T, and 9T variants of the splice acceptor site in intron 8 and F508C, I507V, and I506V (exon 10) polymorphisms of the CFTR gene. Login to comment

PMID: 11100963 [PubMed] Choo-Kang LR et al: "Type I, II, III, IV, and V cystic fibrosis transmembrane conductance regulator defects and opportunities for therapy."

No. Sentence Comment

37 Molecular fate of CFTR protein Type of genetic defect and example Class-specific potential therapeutic approach Specific clinical examples I No synthesis Nonsense G542X Frameshift 394delTT Splice junction 1717-1G→A Aminoglycoside readthrough of premature termination site Gentamicin II Trafficking block AA deletion ∆F508 Missense N1303K Manipulation of intracellular folding environment (chemical or molecular chaperones) Phenylbutyrate, CPX III Block in regulation Missense G551D Stimulation of membrane localized mutant channel Genistein, MPB- compounds IV Altered conductance Missense R117H Augmentation of mutant channel conductance Milrinone, adenosine nucleotides V Reduced synthesis of normal protein Missense A455E Alternative splicing 3849+10kbC→T Maximal activation of decreased but functionally normal channels Stimulation of mRNA and protein synthesis ? Login to comment
116 Through this mechanism, adenosine indirectly activates wild-type as well as several surface-localized mutant CFTR channels including R117H, A455E, and G1349D. Login to comment
124 Missense mutations that belong to this class include P574H and A455E. Login to comment

PMID: 11388756 [PubMed] Heim RA et al: "Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel."

No. Sentence Comment

110 This difference is unlikely to be due to ascertainment, since the observed frequency of ⌬F508 (29%) is equivalent to the frequency of 30% reported by Abeliovich et al.16 In this study, the detection of an additional three mutations was required to bring the overall detection rate to 95.4% (A455E, R553X, and D1152H). Login to comment

PMID: 11401894 [PubMed] Clancy JP et al: "Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis."

No. Sentence Comment

196 Reports indicate that some CF patients with uncommon alleles (i.e., conduction mutants such as R117H or R334W, or the uncommon A455E allele) may have abnormally elevated sweat [Cl- ] values diagnostic of CF but lower than those of the general CF population (9, 25-27). Login to comment

PMID: 11485629 [PubMed] Joseph PM et al: "Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications."

No. Sentence Comment

338 Further supporting the idea that only a small percentage of cells need be corrected to overcome the life-threatening pulmonary consequencesof CF is the fact that the A455E mutation, which is associated with approximately 5% normal CFTR function, appears to confer a mild pulmonary phenotype (Gan et al., 1995; Davies et al., 1998). Login to comment

PMID: 11491164 [PubMed] Massie RJ et al: "Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C."

No. Sentence Comment

41 Infants with a positive (w60 mmol?L-1 ) or borderline (40 - 60 mmol?L-1 ) sweat chloride and in whom there is an unidentified mutation are referred for an extended mutation analysis which includes: DF508, R117H, G551D, A455E, G542X, N1303K, W1282X, 1717-1, R560T, R347P, R334W, R1162X, S549N, 621z1, 3849z10CwT, and the IVS8 polythymidine sequence. Login to comment

PMID: 11504857 [PubMed] Chen JM et al: "A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models."

No. Sentence Comment

100 Moreover, all of the 11 most common missense mutations or single-amino-acid deletions (i.e., F508del, G551D, N1303K, R117H, R347P, I507del, G85E, R560T, A455E, R334W, and S549N) identified in classic and atypical CF patients worldwide (http://www.genet.sickkids.on.ca/cftr) occur in stringently conserved residues across the 15 CFTR sequences. Login to comment

PMID: 11547256 [PubMed] Lebecque P et al: "[Cystic fibrosis and normal sweat chloride values: a case-report]."

No. Sentence Comment

73 Dans des situations d`hétérozygotie composite, la présence de certaines d`entre elles a pu être associée de manière occasionnelle ou parfois plus consistante avec un taux de chlorure dans la sueur inférieur à 60 voire même (dans de très rares cas) 30 mmol/L. Dans ce singulier petit groupe, figurent notamment les mutations 3 849 + 10kb C→T, A455E, R117H, , R347H, G551S, D1152H. Login to comment

PMID: 11569691 [PubMed] Truninger K et al: "Mutations of the cystic fibrosis gene in patients with chronic pancreatitis."

No. Sentence Comment

56 Using multiplex PCR, 15 genomic fragments were amplified which contain the following mutations: ⌬F508, ⌬I507, Q493X, V520F, 1717-1G3A, G542X, G551D, R553X, R560T, S549R, S549N, 3849 ϩ 10kbC3T, 3849 ϩ 4A3G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621 ϩ 1G3T, R117H, Y122X, 711 ϩ 1G3T; 1078delT, R347P, R347H, R334W, A455E, 1898 ϩ 1G3A, 2183AA3G, 2789 ϩ 5G3A. Login to comment

PMID: 11580305 [PubMed] Bigger B et al: "Perspectives on gene therapy for cystic fibrosis airway disease."

No. Sentence Comment

1262 However, human CFTR mutations such as A455E are associated with ~5% CFTR function and confer only a mild pulmonary phenotype. Login to comment

PMID: 11589722 [PubMed] Walkowiak J et al: "Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency."

No. Sentence Comment

86 Kristidis et al. [10] reported that pancreatic insufficiency strongly correlates also with two alleles of DI507, Q493X, G542X, R553X, W1282X, 621 1 1G-T, 1717±1G-A, 556delA, 3659delC, I148T, G480C, V520F and R560T while one or two mutations such as R117H, R334W, A455E, and P574H were correlated with a pancreatic sufficient phenotype. Login to comment

PMID: 11601754 [PubMed] Davies JC et al: "Gene therapy for cystic fibrosis."

No. Sentence Comment

92 Encouragingly, certain mutations such as A455E, associated with approximately 5% CFTR function, appear to confer a mild pulmonary phenotype [53]. Login to comment
94 However, when considering this issue, it is important to bear in mind that in both the interbred mice and the humans with the A455E genotype, each cell would express low levels of CFTR (5-10%). Login to comment

PMID: 11701644 [PubMed] Scriver CR et al: "Human genetics: lessons from Quebec populations."

No. Sentence Comment

242 Three mutations ( F508, 60%; 621 + 1, 25.5%; A455E, 8.5%) account for 94% of CF chromosomes in the SLSJ population, with 42% of probands being homoallelic (50). Login to comment
245 The A455E allele, prominent in SLSJ, has a mild effect and confers pancreatic sufficiency (138). Login to comment
246 Estimates of inbreeding and kinship coefficients in the SLSJ families harboring F508, 621 + 1, and A455E alleles are somewhat higher than in the general population, and a putative common ancestor for carriers of the A455E allele is claimed (40). Login to comment

PMID: 11883825 [PubMed] Padoan R et al: "Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis."

No. Sentence Comment

34 It was initially performed by polyacrylamide gel electrophoretic (PAGE) analysis for the delF508 mutation, and later by polymerase chain reaction (PCR) and oligonucleotide ligation assay (OLA) (31 mutations: G85E, 621 ‡ 1G ® T, R117H, Y122X, 711 ‡ 1G ® T, 1078delT, R347P, R347H, R334W, A455E, 1898 ‡ 1G ® A, 2183-AA ® G, 2789 ‡ 5G ® A, DelF508, I507del, Q493X, V520F, 1717-1G ® A, G542X, G551D, R553X, R560T, S549R, S549N, 3849 ‡ 10kbC ® T, 3849 ‡ 4A ® G, R1162X, 3659delC, W1282X, 3905insT, N1303K) (14). Login to comment

PMID: 11897640 [PubMed] Lebecque P et al: "Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children."

No. Sentence Comment

69 In the latter study, however, data are likely influenced by the frequency of the A455E mutation in the Dutch population. Login to comment

PMID: 11966405 [PubMed] Sangiuolo F et al: "Towards the pharmacogenomics of cystic fibrosis."

No. Sentence Comment

111 Gentamicin Neomicin (G418) Class II Mutations that fail to be properly processed to a matureglycosylatedform and transported to the apical membrane ∆F508 N1303K P574H A455E PI Defective CFTR processing and trafficking. Login to comment
115 3849 + 10 kb C→→→→T 2789 + 5 G→→→→A 3272-26 A→→→→G A455E 3120 +1 G→→→→A 1811 + 1.6 kb A→→→→G 5T PS Normal CFTR channnels Reduced numbers of normal CFTR Reduced cell surface chloride transport Genistein Milrinone Phenylbutyrate Class VI Nonsense or frameshift mutations causing a 70-100 bp truncation of the C-terminus of the CFTR mutations that impair regulation of other types of ion channels. Login to comment

PMID: 11994102 [PubMed] Eaton TE et al: "Cystic fibrosis transmembrane conductance regulator gene mutations: do they play a role in the aetiology of allergic bronchopulmonary aspergillosis?"

No. Sentence Comment

53 Cystic ®brosis mutation analysis Genomic DNA samples were screened for 16 CF mutations utilizing allelic-speci®c oligonucleotide (ASO) hybridization; ÁF508, ÁI507, R117H, W1282X, 621 IG3T, R334W, R347P, A455E, 1717-IG3A, G542X, 5549N, G551D, R553X, R560T, N1303K and 3849 10KC3T. Login to comment

PMID: 12001283 [PubMed] Schaedel C et al: "Predictors of deterioration of lung function in cystic fibrosis."

No. Sentence Comment

121 TABLE 3CFTR Mutations Associated With Pancreatic Sufficiency in Swedish CF Population Y109C S549I/S549I Y109N S945L R117C N1088D À R75Q R117H G1244E L206W 711 þ 3A !G T338I 1249 À 5A !G A455E 2789 þ 5G ! Login to comment

PMID: 12007216 [PubMed] Bobadilla JL et al: "Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening."

No. Sentence Comment

109 Mutational Arrays, Detection Rates and Methods by Region* Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference Europe Albania ∆F508 (72.4%) C276X (0.7%) 74.5 55.5 4 270/146 CFGAC [1994]; Macek et al. G85E (0.7%) R1070Q (0.7%) [2002] Austria ∆F508 (62.9%) 457TAT→G (1.2%) 76.6 58.7 11 1516/580 Estiville et al. [1997]; Dörk et al. (total) G542X (3.3%) 2183AA→G (0.7%) [2000]; Macek et al. [2002] CFTRdele2,3 (2.1%) N1303K (0.6%) R1162X (1.9%) I148T (0.5%) R553X (1.7%) R117H (0.5%) G551D (1.2%) Austria ∆F508 (74.6%) 2183AA→G (2.4%) 95.3 90.8 8 126 Stuhrmann et al. [1997] (tyrol) R1162X (8.7%) G551D (1.6%) G542X (2.4%) R347P (1.6%) 2789+5G→A (2.4%) Q39X (1.6%) Belarus ∆F508 (61.2%) R553X (0.5%) 75.2 56.6 9 278/188 Dörk et al. [2000]; Macek et al. G542X (4.5%) R334W (0.5%) [2002] CFTRdele2,3 (3.3%) R347P (0.5%) N1303K (3.2%) S549N (0.5%) W1282X (1.0%) Belgium ∆F508 (75.1%) 622-1A→C (0.5%) 100.0 100.0 27 1504/522 Cuppens et al. [1993]; Mercier et G542X (3.5%) G458V (0.5%) al. [1993]; CFGAC [1994]; N1303K (2.7%) 1898+G→C (0.5%) Estivill et al.[1997] R553X (1.7%) G970R (0.5%) 1717-1G→A (1.6%) 4218insT (0.5%) E60X (1.6%) 394delTT (0.5%) W1282X (1.4%) K830X (0.5%) 2183A→G+2184delA (1.2%) E822K (0.5%) W401X (1.0%) 3272-1G→A (0.5%) A455E (1.0%) S1161R (0.5%) 3272-26A→G (1.0%) R1162X (0.5%) S1251N (1.0%) 3750delAG (0.5%) S1235R (0.8%) S1255P (0.5%) ∆I507 (0.6%) Bulgaria ∆F508 (63.6%) R75Q (1.0%) 93.0 86.5 21 948/432 Angelicheva et al. [1997]; (total) N1303K (5.6%) 2183AA→G (0.9%) Estivill et al. [1997]; Macek G542X (3.9%) G1244V+S912L (0.9%) et al. [2002] R347P (2.2%) G85E (0.9%) 1677delTA (2.1%) 2184insA (0.9%) R1070Q (1.8%) L88X+G1069R (0.8%) Q220X (1.2%) 2789+5G→A (0.8%) 3849+10KbC→T (1.1%) G1244E (0.8%) W1282X (1.0%) 1717-1G→A (0.8%) 2176insC (1.0%) Y919C (0.7%) G1069R (1.0%) WORLDWIDEANALYSISOFCFTRMUTATIONS581 Bulgaria 1) DF508 4) 1677delTA - - 6 13 Angelicheva et al. [1997] (ethnic 2) R347P 5) Q493R Turks) 3) G542X 6) L571S - - 1 30 Angelicheva et al. [1997] Bulgaria 1) DF508 (100.0%) (Gypsy) Croatia ∆F508 (64.5%) G551D (1.1%) 72.5 52.6 5 276 Macek et al. [2002] G542X (3.3%) 3849+10KbC→T (0.7%) N1303K (2.9%) Czech ∆F508 (70.0%) 1898+1G→T (2.0%) 89.6 80.3 10 2196/628 CFGAC [1994]; Estiville et al. Republic CFTRdele2,3 (5.5%) 2143delT (1.2%) [1997]; Dörk et al. [2000]; G551D (3.8%) R347P (0.8%) Macek et al. [2002] N1303K (2.9%) 3849+10KbC→T (0.6%) G542X (2.2%) W1282X (0.6%) Denmark ∆F508 (87.5%) G542X (0.7%) 92.3 85.2 6 1888/678 CFGAC [1994]; Schwartz et al. (excluding 394delTT (1.8%) 621+1G→T (0.6%) [1994]; Estiville et al. [1997] Faroe) N1303K (1.1%) 3659delC (0.6%) Estonia ∆F508 (51.7%) R117C (1.7%) 80.2 64.3 10 165/80 Estivill et al. [1997]; Klaassen et 394delTT (13.3%) E217G (1.7%) al. [1998]; Macek et al. S1235R (3.3%) R1066H (1.7%) [2002] 359insT (1.7%) 3659delC (1.7%) I1005R (1.7%) S1169X (1.7%) Finland ∆F508 (46.2%) G542X (1.9%) 78.8 62.1 4 132/52 CFGAC [1994]; Kere et al. 394delTT (28.8%) 3372delA (1.9%) [1994]; Estivill et al. [1997] France ∆F508 (67.7%) 2789+5G→T (0.79%) 79.7 63.6 12 17854/7420 Chevalier-Porst et al. [1994]; (total) G542X (2.94%) 2184delA+2183A→G (0.77%) Estivill et al. [1997]; Claustres et al. [2000]; Guilloud-Bataille N1303K (1.83%) G551D (0.74%) et al. [2000] 1717-1G→A (1.35%) 1078delT (0.63%) W1282X (0.91%) ∆I507 (0.62%) R553X (0.86%) Y122K (0.59%) France ∆F508 (75.8%) R297Q (0.8%) 98.7 97.4 18 599/365 Férec et al. [1992]; Scotet et al. (Brittany) 1078delT (4.0%) R347H (0.8%) [2000] G551D (3.6%) I1234V (0.8%) N1303K (3.0%) R553X (0.8%) R117H (1.7%) 2789+5G→A (0.8%) 3272-26A→G (1.3%) 4005+1G→A (0.7%) G542X (1.1%) 621+1G→T (0.6%) 1717-1G→A (1.0%) ∆I507 (0.6%) G1249R (0.8%) W846X (0.5%) France ∆F508 (70.0%) N1303K (0.8%) 90.4 81.7 16 250 Claustres et al. [1993] (southern) G542X (6.4%) 3737delA (0.8%) 1717-1G→A (1.6%) R1162X (0.8%) L206W (1.2%) Y1092X (0.8%) R334W (1.2%) S945L (0.8%) ∆I507 (1.2%) K710X (0.8%) 2184delA (1.2%) 1078delT (0.8%) R1158X (1.2%) Y122X (0.8%) (Continued) BOBADILLAETAL. Login to comment
110 Germany ∆F508 (71.8%) 1789+5G→A (0.9%) 87.6 76.7 17 5662/1316 Dörk et al. [1992]; Dörk et al. R553X (2.0%) 3272-26A→G (0.9%) [1994]; Tümmler et al. [1996]; N1303K (1.8%) W1282X (0.7%) Estivill et al. [1997]; Dörk et G542X (1.2%) 2143delT (0.7%) al. [2000] R347P (1.2%) 1078delT (0.6%) CFTRdele2,3 (1.2%) 2183AA→G (0.6%) 3849+10KbC→T (1.0%) 2184insA (0.6%) G551D (0.9% 3659delC (0.6%) 1717-1G→A (0.9%) Greece ∆F508 (52.9%) 3272-26A→G (0.8%) 82.2 67.6 22 2097/718 Kanavakis et al. [1995]; Estivill 621+1G→T (5.0%) R1070Q (0.8%) et al. [1997]; Tzetis et al. G542X (4.1%) W496X (0.7%) [1997]; Macek et al. [2002] N1303K (3.3%) 621+3A→G (0.7%) 2183AA→G (1.8%) ∆I507 (0.7%) 2789+5G→A (1.7%) W1282X (0.7%) E822X (1.6%) 574delA (0.7%) R117H (1.2%) 1677delTA (0.7%) R334W (1.1%) A46D (0.6%) R1158X (1.0%) 3120+1G→A (0.6%) G85E (1.0%) G551D (0.5%) Hungary ∆F508 (54.9%) W1282X (1.8%) 68.3 46.6 9 1133/976 CFGAC [1994]; Estivill et al. 1717-1G→A (1.9%) G542X (1.7%) [1997]; Macek et al. [2002] R553X (2.1%) N1303K (1.3%) Y1092X (1.8%) G551D (1.0%) S1196X (1.8%) Ireland ∆F508 (70.4%) G542X (1.0%) 82.1 67.4 7 801/509 CFGAC [1994]; Estivill et al. G551D (5.7%) 621+1G→T (0.8%) [1994] R117H (2.4%) 1717-1G→A (0.6%) R560T (1.2%) Italy ∆F508 (50.9%) ∆I507 (0.65%) 60.3 36.4 9 3524 Estivill et al. [1997] (total) G542X (3.1%) W1282X (0.62%) 1717-1G→A (1.6%) Y122K (0.59%) N1303K (1.4%) G551D (0.53%) R553X (0.94%) Italy ∆F508 (47.6%) R553X (1.3%) 87.1 75.9 15 225 Bonizzato et al. [1995] (Northeast) R1162X (9.8%) 2789+G→A (1.3%) 2183AA→G (9.3%) Q552X (1.3%) N1303K (4.0%) 621+1G→T (0.9%) G542X (2.7%) W1282X (0.9%) 711+5G→A (2.7%) 3132delTG (0.9%) 1717-1G→A (2.2%) 2790-2A→G (0.9%) G85E (1.3%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS583 Italy ∆F508 (56.4%) 711+1G→T (1.3%) 85.7 73.4 13 660/396 Castaldo et al. [1996]; Castaldo (southern) N1303K (6.8%) G1244E (1.3%) et al. [1999] G542X (5.7%) R1185X (1.3%) W1282X (3.8%) L1065P (1.3%) 1717-1G→A (2.3%) R553X (1.1%) 2183AA→G (1.9%) I148T (0.7%) 4016insT (1.8%) Latvia 1) DF508 (58.3%) 4) CFTRdele2,3 (2.8%) - - 6 36 Dörk et al. [2000]; Macek et al. 2) 3849+10KbC®T (8.3%) 5) W1282X (2.8%) [2002] 3) N1303K (5.6%) 6) 394delTT (2.8%) Lithuania ∆F508 (31.0%) N1303K (2.0%) 39.0 15.2 4 94 Dörk et al. [2000]; Macek et al. R553X (4.0%) CFTRdele2,3 (2.0%) [2002] Macedonia ∆F508 (54.3%) 711+3A→G (1.0%) 69.2 47.9 12 559/226 Petreska et al. [1998]; Dörk et G542X (4.2%) 3849G→A (1.0%) al. [2000]; Macek et al. N1303K (2.0%) 2184insA (0.9%) [2002] CFTRdele2,3 (1.3%) 457TAT→G (0.7%) 621+1G→T (1.3%) V139E (0.7%) 611-1G→T (1.2%) 1811+1G→C (0.6%) Netherlands ∆F508 (74.2%) R1162X (0.9%) 86.8 75.3 9 3167/1442 Gan et al. [1995]; Estiville et al. A455E (4.7%) S1251N (0.9%) [1997]; Collee et al. [1998] G542X (1.8%) N1303K (0.9%) 1717-1G→A (1.5%) W1282X (0.7%) R553X (1.2%) Norway ∆F508 (60.2%) G551D (1.2%) 69.8 48.7 6 410/242 Schwartz et al. [1994]; Estivill 394delTT (4.2%) G542X (0.6%) et al. [1997] R117H (3.0%) N1303K (0.6%) Poland ∆F508 (57.1%) CFTRdele2,3 (1.8%) 73.5 54.0 11 4046/1726 CFGAC [1994]; Estivill et al. 3849+10Kb C→T (2.7%) R560T (1.5%) [1997]; Dörk et al [2000]; G542X (2.6%) W1282X (0.7%) Macek et al. [2002] 1717-1G→A (2.4%) ∆I507 (0.5%) R553X (1.9%) G551D (0.5%) N1303K (1.8%) Portugal ∆F508 (44.7%) R334W (0.7%) 49.7 24.7 5 739/454 CFGAC [1994]; Estivill et al. G542X (1.6%) N1303K (0.7%) [1997] R1066C (2.0%) Romania ∆F508 (36.6%) G542X (1.4%) 51.5 26.5 11 224/74 CFGAC [1994]; Estivill et al. 2043delG (2.0%) R553X (1.4%) [1997]; Popa et al. [1997]; W1282X (1.7%) G576X (1.4%) Macek et al. [2002] 1717-2A→G (1.4%) 1898+1G→A (1.4%) I148T (1.4%) 2183AA→G (1.4%) 621+1G→T (1.4%) Russia ∆F508 (54.4%) 552insA (0.9%) 70.7 50.0 12 5073/2562 CFGAC [1994]; Estivill et al. CFTRdele2,3 (5.0%) G542X (0.9%) [1997]; Dörk et al. [2000]; R553X (3.5%) R334W (0.9%) Macek et al. [2002] 2183AA→G (1.3%) 1677delTA (0.8%) W1282X (1.0%) Y122X (0.5%) 394delTT (1.0%) 1367del5 (0.5%) (Continued) BOBADILLAETAL. Login to comment
112 Jewish 1) 405+1G®A (48.0%) 3) W1282X (17.0%) - - 4 23 Kerem et al. [1995] (Tunisia) 2) DF508 (31.0%) 4) 3849+10KbC®T (4.0%) Jewish 1) G85E 4) G542X - - 6 10 Kerem et al. [1995] (Turkey) 2) DF508 5) 3849+10KbC®T 3) W1282X 6) W1089X Jewish (Yemen) None - - 0 5 Kerem et al. [1995] Lebanon 1) DF508 (35.0%) 6) 4096-28G®A (2.5%) - - 9 40 Desgeorges et al. [1997] 2) W1282X (20.0%) 7) 2789+5G®A (2.5%) 3) 4010del4 (10.0%) 8) M952I (2.5%) 4) N1303K (10.0%) 9) E672del (2.5%) 5) S4X (5.0%) Reunion ∆F508 (52.0%) 1717-1G→A (0.7%) 90.4 81.7 9 138 Cartault et al. [1996] Island Y122X (24.0%) G542X (0.7%) 3120+1G→A (8.0%) A309G (0.7%) A455E (2.2%) 2789+5G→A (0.7%) G551D (1.4%) Saudi North: 3) H139L - - North 1 49 families El-Harith et al. [1997]; Arabia 1) 1548delG 4) L1177X Central 3 Kambouris et al. [1997]; Central: 5) DF508 South 4 Banjar et al. [1999] 1)I1234V 6) 3120+1G®A West 9 2)1548delG 7) 425del42 East 6 3)DF508 8) R553X South: 9) N1303K 1) I1234V East: 2) 1548delG 1) 3120+1G®A 3) 711+1G®T 2) H139L 4) 3120+1G®A 3) 1548delG West: 4) DF508 1) I1234V 5) S549R 2) G115X 6) N1303K Tunisia ∆F508 (17.6%) G85E (2.6%) 58.7 34.5 11 78 Messaoud et al. [1996] G542X (8.9%) W1282X (2.6%) 711+1G→T (7.7%) Y122X (1.3%) N1303K (6.4%) T665S (1.3%) 2766del8NT (6.4%) R47W+D1270N (1.3%) R1066C (2.6%) Turkeye ∆F508 (24.5%) 1066L (1.3%) 80.6 65.0 36 1067/670 Yilmaz et al. [1995]; Estivill et al. 1677delTA (4.1%) E822X (1.3%) [1997]; Onay et al. [1998]; 2789+5G→A (3.9%) 2183+5G→A+2184insA (1.3%) Macek et al. [2002] 2181delA (3.8%) D110H (0.8%) R347H (3.6%) P1013L (0.8%) N1303K (2.9%) 3172delAC (0.8%) 621+1G→T (2.6%) 1259insA (0.8%) G542X (2.6%) M1028I (0.8%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS587 E92K (2.6%) 4005+1G→A (0.7%) A96E (2.6%) W1282X (0.7%) M152V (2.6%) I148T (0.6%) 2183AA→G (2.5%) R1162X (0.6%) 296+9A→T (1.6%) D1152H (0.6%) 2043delG (1.4%) W1098X (0.6%) E92X (1.4%) E831X (0.6%) K68N (1.4%) W496X (0.6%) G85E (1.3%) F1052V (0.5%) R1158X (1.3%) L571S (0.5%) United Arab S549R (61.5%) ∆F508 (26.9%) 88.4 78.1 2 86/52 Frossard et al. [1988]; Emirates Frossard et al. [1999] North/Central/South Americas Argentina ∆F508 (58.6%) N1303K (1.8%) 69.1 47.7 5 326/228 CFGAC [1994]; Chertkoff et al. W1282X (3.9%) 1717-1G→A (0.9%) [1997] G542X (3.9%) Brazilf ∆F508 (47.7%) W1282X (1.3%) 66.8 44.6 10 820/500 CFGAC [1994]; Cabello et al. (total) G542X (7.2%) G85E (1.3%) [1999]; Raskin et al. [1999]; R1162X (2.5%) R553X (0.7%) Bernardino et al. [2000] R334W (2.5%) L206W (0.6%) N1303K (2.4%) 2347delG (0.6%) South East: >∆F508, G542X South: >N1303K Brazil ∆F508 (31.7%) N1303K (2.5%) 42.5 18.1 3 120 Parizotto and Bertuzzo [1997] (Sao Paulo) G542X (8.3%) Canada ∆F508 (59.0%) G542X (0.5%) 98.5 97.0 13 381/200 Rozen et al. [1992]; (Lac St. Jean) 621+1G→T (24.3%) N1303K (0.5%) De Braekeleer et al. [1998] A445E (8.2%) Q890X (0.5%) Y1092X (1.2%) S489X (0.5) 711+1G→T (1.0%) R117C (0.5%) I148T (1.0%) R1158 (0.5%) G85E (0.8%) Canada ∆F508 (71.4%) ∆I507 (1.3%) 90.9 82.6 7 77 Rozen et al. [1992] (Quebec City) 711+1G→T (9.1%) Y1092X (1.3%) 621+1G→T (5.2%) N1303K (1.3%) A455E (1.3%) Canada ∆F508 (70.9%) W1282X (0.9%) 82.0 67.2 10 632 Kristidis et al. [1992] (Toronto) G551D (3.1%) R117H (0.9%) G542X (2.2%) 1717-1G→A (0.6%) 621+1G→T (1.3%) R560T (0.6%) N1303K (0.9%) ∆I507 (0.6%) Chile ∆F508 (29.2%) R553X (4.2%) 33.4 11.2 2 72 Rios et al. [1994] Columbia 1) DF508 (35.4%) 3) N1303K (2.1%) - - 4 48 Restrepo et al. [2000] 2) G542X (6.3%) 4) W1282X (2.1%) Ecuador 1) DF508 (25%) - - 1 20 Paz-y-Mino et al. [1999] (Continued) BOBADILLAETAL. Login to comment
113 Mexico ∆F508 (41.6%) G551S (0.5%) 75.5 57.0 35 374/194 Orozco et al.[1993]; Villalobos- G542X (5.6%) 1078delT (0.5%) Torres et al. [1997]; Liang et al. ∆I507 (2.5%) Y1092X (0.5%) [1998]; Orozco et al. [2000] S549N (1.9%) R117H (0.5%) N1303K (1.7%) G85E (0.5%) R75X (1.5%) 1716G→A (0.5%) 406-1G→A (1.5%) W1204X (0.5%) I148T (1.5%) W1098C (0.5%) 3849+10KbC→T (1.5%) 846delT (0.5%) 621+1G→T (1.2%) P750L (0.5%) 2055del9→A (1.0%) V754M (0.5%) 935delA (1.0%) R75Q (0.5%) I506T (1.0) W1096X (0.5%) 3199del6 (1.0%) L558S (0.5%) 2183AA→G (1.0%) 4160insGGGG (0.5%) G551D (0.5%) 297-1G→A (0.5%) R553X (0.5%) H199Y (0.5%) 1924del7 (0.5%) United States ∆F508 (68.6%) R553X (0.9%) 79.7 63.5 10 25048 Cystic Fibrosis Foundation (total) G542X (2.4%) 621+1G→T (0.9%) [1998] G551D (2.1%) 1717-1G→A (0.7%) W1282X (1.4%) 3849+10KbC→T (0.7%) N1303K (1.3%) R117H (0.7%) United States ∆F508 (48.0%) S1255X (1.4%) 77.3 59.8 16 160/148 Carles et al. [1996]; Macek et al. (African 3120+1G→A (12.2%) 444delA (0.7%) [1997]; Dörk et al. [1998]; American) 2307insA (2.0%) R334W (0.7%) Friedman et al. [1998] A559T (2.0%) ∆I507 (0.7%) R553X (2.0%) 1717-1G→A (0.7%) ∆F311 (2.0%) G542X (0.7%) G480C (1.4%) S549N (0.7%) 405+3A→C (1.4%) G551D (0.7%) United States 1) L1093P - - 1 2 Yee et al. [2000] (Cherokee) United States Non-French: French: Non- Non- Non- Non- Bayleran et al. [1996] (Maine) ∆F508 (82.0%) ∆F508 (58%) French: French: French: French: G542X (2.6%) 711+1G→T (8.3%) 95.3 90.8 11 191 G551D (2.6%) I148T (4.2%) French: French: French: French: N1303K (2.1%) A455E (4.2%) 80.3 64.5 8 72 R560T (1.0%) 1717-1G→A (1.4%) Total: 621+1G→T (1.0%) G85E (1.4%) 263 711+1G→T (1.0%) 621+1G→T (1.4%) R117H (1.0%) Y1092X (1.4%) 1717-1G→A (1.0%) G85E (0.5%) W1282X (0.5%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS589 United States ∆F508 (46.0%) R334W (1.6%) 58.5 34.2 7 129 Grebe et al. [1994] (SW Hispanic) G542X (5.4%) W1282X (0.8%) 3849+10KbC→T (2.3%) R553X (0.8%) R1162X (1.6%) United States 1) R1162X - - 3 17 Mercier et al. [1992] (SW Native 2) D648V American) 3) G542X United States 1) R1162X 3) G542X - - 4 16 Mercier et al. [1994] (Zuni Pueblo) 2) 3849+10KbC®T 4) D648V Venezuela ∆F508 (29.6%) G542X (3.7%) 33.3 11.1 2 54 Restrepo et al. [2000] Other Regions Australia ∆F508 (76.9%) 621+1G→T (1.1%) 88.7 78.7 8 761/464 CFGAC [1994] G551D (4.5%) N1303K (0.9%) G542X (2.8%) W1282X (0.6%) R553X (1.3%) R117H (0.6%) East Asia 1) 1898+1G®T 2) 1898+5G®T - - 2 28 Suwanjutha et al. [1998] Hutterite 1) M1101K (69.0%) 2) DF508 (31.0%) - - 2 32 Zielenski et al. [1993] Brethren New Zealand ∆F508 (78.0%) N1303K (1.9%) 87.4 76.4 5 636 CFGAC [1994] G551D (4.4%) 621+1G→T (1.1%) G542X (2.0%) *This table presents the mutation panels for all regions investigated in this study. Login to comment
213 Ideal Recommended CFTR Mutation Screening Panel for 2001 Neonatal Screening in the USA* Location Estimated Mutation in CFTRa percentageb Reason for inclusion DF508 Exon 10 68.6% CFF registry, >1%, Pan-European G542X Exon 11 2.4% CFF registry, >1%, Mediterranean G551D Exon 11 2.1% CFF registry, >1%, Celtic W1282X Exon 20 1.4% CFF registry, >1%, Ashkenazi Jew N1303K Exon 21 1.3% CFF registry, >1%, Mediterranean R553X Exon 11 0.9% CFF registry, >0.5%, Hispanic 621+1G®T Intron 4 0.9% CFF registry, >0.5%, multi-ethnic 1717-1G®A Intron 10 0.7% CFF registry, >0.5%, Italian 3849+10KbC®T Intron 19 0.7% CFF registry, >0.5%, Hispanic R117Hc Exon 4 0.7% CFF registry, >0.5% 1898+1G→T Intron 12 0.4% CFF registry, >0.1%, East Asian DI507 Exon 10 0.3% CFF registry, >0.1%, Hispanic 2789+5G®A Intron 14b 0.3% CFF registry, >0.1% G85E Exon 3 0.3% CFF registry, >0.1% R347P Exon 7 0.2% CFF registry, >0.1% R334W Exon 7 0.2% CFF registry, >0.1%, multi-ethnic R1162X Exon 19 0.2% CFF registry, >0.1%, multi-ethnic R560T Exon 11 0.2% CFF registry, >0.1% 3659delC Exon 19 0.2% CFF registry, >0.1% A455E Exon 9 0.2% CFF registry, >0.1% 2184delA Exon 13 0.1% CFF registry, >0.1% S549N Exon 11 0.1% CFF registry, >0.1%, multi-ethnic 711+1G®T Intron 5 0.1% CFF registry, >0.1% R75X Exon 3 0.2% Hispanic 406-1G→A Intron 3 0.2% Hispanic I148T Exon 4 0.2% Hispanic, French 2055del9→A Exon 13 0.1% Hispanic 935delA Exon 6b 0.1% Hispanic I506T Exon 10 0.1% Hispanic 3199del6 Exon 17a 0.1% Hispanic 2183AA→G Exon 13 0.1% Hispanic 3120+1G®A Intron 16 1.5% African American, Arabian 2307insA Exon 13 0.2% African American A559T Exon 11 0.2% African American ∆F311 Exon 7 0.2% African American G480C Exon 10 0.2% African American 405+3A→C Intron 3 0.2% African American S1255X Exon 20 0.2% African American L1093P Exon 17b Undetermined Native American D648V Exon 13 Undetermined Native American I1234V Exon 19 Undetermined Arabian linkage S549R Exon 11 Undetermined Arabian linkage 1898+5G→T Intron 12 Undetermined East Asian linkage CFTRdele2,3 Exons 2,3 Undetermined Eastern European linkage (Slavic) Y1092X Exon 17b Undetermined French linkage 394delTT Exon 3 Undetermined Nordic linkage Y569D Exon 12 Undetermined Pakistani linkage 3905insT Exon 20 Undetermined Swiss linkage (also: Amish, Acadian, Mennonite) 1898+1G®A Intron 12 Undetermined Welsh linkage M1101k Exon 17b Undetermined Hutterite ancestry *This table presents the top 50 mutations in the USA based on the Cystic Fibrosis Foundation CF Registry data from 1997 [Cystic Fibrosis Foundation, 1998], and data generated during our investigation. Login to comment

PMID: 12014388 [PubMed] Padoan R et al: "Negative sweat test in hypertrypsinaemic infants with cystic fibrosis carrying rare CFTR mutations."

No. Sentence Comment

14 Diagnostic delay has been reported for patients bearing specific CFTR gene mutations such as R117H, D1152H, 3849+10kbCfiT, A455E and 2789+5GfiA, which were associated with a non-pathological sweat chloride level [3, 6, 9,13]. Login to comment

PMID: 12089190 [PubMed] Wang X et al: "Development and evaluation of a PCR-based, line probe assay for the detection of 58 alleles in the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

68 Amplicon Size, bp Mutations (polymorphisms) Exon 13 598 2307 insA Intron 8, exon 09 548 A455E, 5T (7/9 T polymorphism) Exon 10 482 G480C, ⌬I507, ⌬F508 (F508C, I507V, I506V polymorphisms) Intron 10, exon 11 433 1717-1G3A, G542X, G551D, R553X, A559T, R560T Exon 19 420 R1162X, 3659delC Exon 21 397 N1303K Exon 20 359 S1255X, W1282X Exon 07 328 1078delT, R334W, R347P Exon 04, intron 4 288 R117H, 621ϩ1G3T Intron 14b 248 2789ϩ5G3A Intron 19 237 3849ϩ10kbC3T Exon 03 210 G85E, 405ϩ3A3C Intron 5 166 711ϩ1G3T Intron 16 139 3120ϩ1G3A Clinical Chemistry 48, No. Login to comment
80 The signal intensities of the wild-type alleles for A455E, G480C, I507/F508, and 2307insA probes were decreased when 12.5 ng of DNA was used, but could still be distinguished from background even at 6.25 ng of DNA. Login to comment
88 The genotypes of each sample are as follows: lane 1, ϩ/ϩ (ϩ is the wild type); lane 2, 5T, R117H/3659delC; lane 3, G542X/ϩ; lane 4, I506V/ϩ; lane 5, I507V/ϩ; lane 6, F508C/⌬F508; lane 7, G85E/⌬F508; lane 8, 405ϩ3A3C/3120ϩ1G3C; lane 9, R117H/ϩ; lane 10, 621ϩ1G3T/⌬F508; lane 11, 711ϩ1G3T/⌬F508; lane 12, 1078delT/ϩ; lane 13, R334W/⌬F508; lane 14, R347P/⌬F508; lane 15, A455E/ϩ; lane 16, G480C/⌬F508; lane 17, ⌬I507/ϩ; lane 18, ⌬F508/ϩ; lane 19, 1717-1G3A/ϩ; lane 20, G542X/ϩ; lane 21, G551D/⌬F508; lane 22, R553X/ϩ; lane 23, R560T/⌬F508; lane 24, G551D/A559T; lane 25, 2307insA/ϩ; lane 26, 2789ϩ5G3A/⌬F508; lane 27, 3120ϩ1G3A/⌬F508; lane 28, R1162X/R1162X; lane 29, 3659delC/⌬F508; lane 30, 3849ϩ10kbC3T/⌬F508; lane 31, S1255X/⌬F508; lane 32, W1282X/G542X; lane 33, N1303K/ϩ. Login to comment

PMID: 12116247 [PubMed] Muller F et al: "Predicting the risk of cystic fibrosis with abnormal ultrasound signs of fetal bowel: results of a French molecular collaborative study based on 641 prospective cases."

No. Sentence Comment

52 T, 1078delT, R347P, R347H, R334W, A455E, 1898 þ 1G ! Login to comment

PMID: 12124743 [PubMed] Salvatore F et al: "Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes."

No. Sentence Comment

46 A series of mutations usually associated with pancreatic sufficiency have been identified and defined as ''mild`` with reference to pancreatic status [Kerem et al., 1989c]: G85E, G91R, R117H, E193K, P205S, R334W, T338I, R347H, R347L, R347P, R352Q, A455E, S492F, S549N, P574H, D579G, 711 þ 5 G > A, C866Y, F1052V, H1054D, R1066H, R1068H, H1085R, D1152H, S1159P, S1251N, F1286S, G1349D, 2789 þ 5 G > A, and 3849 þ 10kb C > T [Dean et al., 1990; Cutting et al., 1990a; Cremonesi et al., 1992; Highsmith et al., 1994]. Login to comment
59 Several findings suggest that the pulmonary phenotype is directly related to the CFTR genotype: 1) missense mutations (e.g., R117H and A455E) give rise to a milder pulmonary expression [Gan et al., 1995; De Braekeleer et al., 1997]; 2) CF patient homozygotes for DF508 and compound heterozygotes for DF508 and a nonsense mutation at the level of the nucleotide binding folder (NBF) encoding region of the CFTR gene are more susceptible to P. aeruginosa infections [Kubesch et al., 1993; Davidson et al., 1995]; and 3) CF patient homozygotes for DF508 invariably have a severe pulmonary phenotype [Johansen et al., 1991]. Login to comment

PMID: 12133923 [PubMed] Corbetta C et al: "Screening for cystic fibrosis in newborn infants: results of a pilot programme based on a two tier protocol (IRT/DNA/IRT) in the Italian population."

No. Sentence Comment

266 Mutations identified by the assay are G85E, 621+1G→T, R117H, Y122X, 711+1G→T, 1078delT, R347P, R347H, R334W, A455E, 1898+1G→A, 2183-AA→G, 2789+5G→A, delF508, I507del, Q493X, V520F, 1717-1G→A, G542X, G551D, R553X, R560T, S549R, S549N, 3849+10kbC→T, 3849+4A→G, R1162X, 3659delC, W1282X, 3905insT, and N1303K. Login to comment

PMID: 12151438 [PubMed] Wang Z et al: "Analysis by mass spectrometry of 100 cystic fibrosis gene mutations in 92 patients with congenital bilateral absence of the vas deferens."

No. Sentence Comment

20 Given the frequency of CF mutations, especially in the Caucasian population ( in 25), and the common request by CBAVD men to sire their own offspring by using surgical Table I. The 100 most common cystic fibrosis mutations listed by exon Mutationa Exonb Frequency (%)c G85E 3 0.1 394delTT 3 Swedish E60X 3 Belgium R75X 3 405ϩ1G→A Int 3 R117H 4 0.30 Y122X 4 French 457TAT→G 4 Austria I148T 4 Canada (French Canadian) 574delA 4 444delA 4 R117L 4 621ϩ1G→T Int 4 0.72 711ϩ1G→T Int 5 Ͼ0.1 712-1G→T Int 5 711ϩ5G→A Int 5 Italy (Caucasian) L206W 6a R347P 7 0.24 1078delT 7 Ͼ0.1 R334W 7 Ͼ0.1 1154InsTC 7 T338I 7 Italy R347H 7 Turkey Q359K/T360K 7 Israel (Georgian Jews) I336K 7 R352Q 7 G330X 7 S364P 7 A455E 9 0.20 I507 10 0.21 F508 10 66.02 1609delCA 10 Spain (Caucasian) V520F 10 Q493X 10 C524X 10 G480C 10 Q493R 10 1717-1G→A Int 10 0.58 R553X 11 0.73 G551D 11 1.64 G542X 11 2.42 R560T 11 Ͼ0.1 S549N 11 Q552X 11 Italy S549I 11 Israel (Arabs) A559T 11 African American R553G 11 R560K 11 1812-1G→A Int 11 A561E 12 E585X 12 Y563D 12 Y563N 12 1898ϩ1G→A Int 12 0.22 1898ϩ1G→C Int 12 2183AA→G 13 Italian 2184delA 13 Ͻ0.1 K710X 13 2143delT 13 Moscow (Russian) 2184InsA 13 1949del84 13 Spain (Spanish) 2176InsC 13 2043delG 13 2307insA 13 2789ϩ5G→A Int 14b Ͼ0.1 2869insG 15 S945L 15 Q890X 15 3120G→A 16 2067 Table I. continued Mutationa Exonb Frequency (%)c 3120ϩ1G→A Int 16 African American 3272-26A→G Int 17a R1066C 17b Portugal (Portugese) L1077P 17b R1070Q 17b Bulgarian W1089X 17b M1101K 17b Canada (Hutterite) R1070P 17b R1162X 19 0.29 3659delC 19 Ͼ0.1 3849G→A 19 3662delA 19 3791delC 19 3821delT 19 Russian Q1238X 19 S1235R 19 France, South S1196X 19 K1177R 19 3849ϩ10kbC→T Int 19 0.24 3849ϩ4A→G Int 19 W1282X 20 1.22 S1251N 20 Dutch, Belgian 3905insT 20 Swiss, Acadian, Amish G1244E 20 R1283M 20 Welsh W1282R 20 D1270N 20 S1255X 20 African American 4005ϩ1G→A Int 20 N1303K 21 1.34 W1316X 21 aMutations were chosen according to their frequencies (Cystic Fibrosis Genetic Analysis Consortium, 1994; Zielenski and Tsui, 1995; Estivill et al., 1997). Login to comment
35 ACMG 25 mutation panel (ACMG25): The following mutations are the recommended core mutations for general population CF carrier screening by American College of Medical Genetics (ACMG) (Grody, et al 2001): ∆F508, G542X, N1303K, G551D, W1282X, 1717-1G→A, R553X, 621ϩ1G→T, R1162X, R117H, ∆I507, 1898ϩ1G→A, G85E, R347P, A455E, R560T, R334W, 3849ϩ10kbC→T, 3659delC, 1078delT, 2789ϩ5G→A, 711ϩ1G→T, 2184delA, 3120ϩ1G→A and I148T. Login to comment
86 CFTR mutations in 92 men with congenital bilateral absence of vas deferens Mutations CFTR mutation panels CF25 CF25 ϩ 5T ACMG25 ACMG25 ϩ 5T CF100 Mutations detected in ∆F508 39 39 39 39 39 CF25 mutation panel R117H 4 4 4 4 4 W1282X 4 4 4 4 4 G551D 3 3 3 3 3 G542X 1 1 1 1 1 N1303K 1 1 1 1 1 IVS8-polyT IVS8-5T 33 33 33 Additional mutations L206W 3 detected not in CF25 D1270N 2 mutation panel 1154InsTC 1 3272-26A→G 1 A455E 1 1 1 R334W 1 1 1 Q890X 1 Total 14 52 85 54 87 95 respectively, in the total number of patients with at least one mutation. Login to comment
91 CFTR genotypes in 92 men with congenital bilateral absence of vas deferens Genotypesa CFTR mutation panelsb CF25 CF25 ϩ 5T ACMG25 ACMG25 ϩ 5T CF100 Two mutations ∆F508/5T 16 16 16 W1282X/5T 4 4 4 ∆F508/R117Hc 3 3 3 3 3 G542X/5T 1 1 1 G551D/5T 1 1 1 ∆F508/L206W 2 ∆F508/A455E 1 1 1 ∆F508/3272-26A→G 1 Q890X/5T 1 L206W/5T 1 D1270N/D1270N 1 5T/5T 1 1 1 Sub-total 3 26 4 27 33 One mutation ∆F508/ϩ 36 20 35 19 16 5T/ϩ 9 9 7 G551D/ϩ 3 2 3 2 2 G542X/ϩ 1 1 R117H/ϩ 1 1 1 1 1 N1303K/ϩ 1 1 1 1 1 W1282X/ϩ 4 4 R334W/ϩ 1 1 1 1154InsTC/ϩ 1 Sub-total 46 33 46 33 29 Total (%) 49 (53.3) 59 (64.1) 50 (54.3) 60 (65.2) 62 (67.4) No mutation (%) 43 (46.7) 33 (35.9) 42 (45.7) 32 (34.8) 30 (32.6) aMutations L206W, 3272-26A→G, Q890X, D1270N, 1154InsTC and 5T are not in either CF25 and ACMG25 panels, while A455E and R334W are not in CF25, but are part of ACMG25 panel. Login to comment

PMID: 12216276 [PubMed] Davies JC et al: "New therapeutic approaches for cystic fibrosis lung disease."

No. Sentence Comment

70 Also, certain mutations such as A455E, associated with approximately 5% CFTR function, appear to confer a mild pulmonary phenotype27. Login to comment

PMID: 12357328 [PubMed] McCormick J et al: "Demographics of the UK cystic fibrosis population: implications for neonatal screening."

No. Sentence Comment

83 The additional eleven are S549N, 3849+4A?G, 3905insT, 2789+5G?A, Y122X, 711+1G?T, R347P, R347H, R334W, A455E and 3281AA?G. Login to comment

PMID: 12394352 [PubMed] Richards CS et al: "Standards and guidelines for CFTR mutation testing."

No. Sentence Comment

60 Examples of such mutations include R117H, 3849 ϩ 10 kbCϾT, A455E, 2789 ϩ 5GϾA, G85E, and R334W. Login to comment
307 ⌬F508 R553X R1162X 2184delA 3120ϩ1GϾA ⌬I507 G542X G551D W1282X N1303K 621ϩ1GϾT R117H 1717-1GϾA A455E R560T G85E R334W R347P 711ϩ1GϾT 1898ϩ1GϾA 1078delT 3849ϩ10kbCϾT 2789ϩ5GϾA 3659delC I148T CF 3.3.2 Inclusion of the common R117H mutation in the test panel screens for CBAVD as well as for CF: The phenotypic consequences of the R117H mutation are modulated in cis by the 5/7/9T polypyrimidine tract in intron 8 such that R117H/7T is associated with CBAVD and R117H/5T is associated with CF.34 Moreover, the 5T allele is associated as a trans mutation in CBAVD.35 It is recommended that the 5/7/9T variant be excluded from the routine carrier screen but tested as a reflex for carriers shown to be heterozygous for the R117H mutation. Login to comment

PMID: 12403872 [PubMed] Tate S et al: "Airways in cystic fibrosis are acidified: detection by exhaled breath condensate."

No. Sentence Comment

240 Choi et al11 showed that cultured cells expressing CFTR mutations known to be associated with pancreatic sufficiency (class 4-5 mutations such as R117H, A455E) displayed significantly greater bicarbonate conductance than mutations associated with pancreatic insufficiency (class 1-3 mutations, G452X, ∆F508, G551D). Login to comment

PMID: 12437773 [PubMed] Huber K et al: "Survey of CF mutations in the clinical laboratory."

No. Sentence Comment

35 All probands (or their par- Table 1: Exons and introns that are amplified with the line probe assay, and the mutations they encompass Roche assay: Amplicon Mutations exon 4 R117H,621+1G → T exon 7 R334W, R347P exon 9 A455E, 5/7/9T polymorphism exon 10 ∆1507, ∆F508. Login to comment
36 F508C, I507V, I506V polymorphism exon 11 1717-1G → A, G542X, S549N, G551D, R553X, R560T exon 20 W1282X exon 21 N1303K intron 19 3849+10kb C → T Innogenetics assay: exon 3 394delTT, G85E, E60X exon/intron 4 621+1G-T, R117H exon 7 1078delT, R347P, R334W exon 13 2143delT, 2183AA-G, 2184delA exon 19 R1162X, 3659delC intron 5 711+5G-A intron8/exon 9 A455E,, 5T,7T,9T intron 14b 2789+5G-A intron 19 3849+10kb C-T Table 2: Genotypes of patients with mutations, final results Group 1) (patients with symptoms typical for/indicative of CF) No. Login to comment

PMID: 12544470 [PubMed] Strom CM et al: "Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test."

No. Sentence Comment

72 Seven of the nine involved the A455E mutation, and the remaining two involved the 1898 ϩ 1 G3A mutation. Login to comment
73 Weak positive lines for the A455E mutation were observed in five instances. Login to comment
75 Sequencing analysis revealed novel missense mutations or sequence variations in all five cases: two patients had 1508 C3T (S459F) occurring four codons upstream from A455E, two had 1496 C3T (A455 V), and one had 1520G3A (G463D). Login to comment
76 Whether these base changes represent novel CF mutations or polymorphism cannot be determined at this time, but the sequence analysis prevented the misdiagnosis of the patients as heterozygotes for A455E. Login to comment
77 In two cases there was no A455E signal in either the mutant or wild-type line. Login to comment
81 Because of these unusual results at the A455E site, we sequenced that exon for every patient previously found to be heterozygous for A455E. Login to comment
82 Ten patients were sequenced and the genotype A455E/wt was confirmed, indicating that the assay performance for this allele is acceptable when the expected intensity of the mutant band is observed. Login to comment
83 These data suggest that caution must be taken when weak A455E mutant bands are observed. Login to comment
90 Table 4 Results of sequencing of patient samples Description Prior genotype Sequencing CommentAllele 1 Allele 2 Confirmed CF wt/delta F508 delta F508 P205S Known mutation Confirmed CF wt/3849 ϩ 10 kb 3849 ϩ 10 kb L1077P Known mutation C 3 T C 3 T Confirmed CF wt/delta F508 delta F508 R1066C Known mutation Confirmed CF wt/delta F508 delta F508 D806G Novel missense Confirmed CF wt/wt 3154delG 3154delG Both parents confirmed carriers Confirmed CF delta F508/wt delta F508 G1244E Known mutation Confirmed CF wt/wt wt F191L Novel missense Borderline sweat test wt/wt wt wt Table 5 Resolution of ambiguities on linear array assay using sequencing Linear array result Resolution Weak mutant A455E line 1508 C 3 T (S459F) polymorphism or novel mutation Weak mutant A455E line 1508 C 3 T (S459F) polymorphism or novel mutation Weak mutant A455E line wt/1496 C 3 T (A455V) polymorphism or novel mutation Weak mutant A455E line wt/1496 C 3 T (A455V) polymorphism or novel mutation Weak mutant A455E line wt/1520 G 3 A (G463D) polymorphism or novel mutation No A455E mutant or wt line Homozygous 1499 T 3 C (V456A) polymorphism or novel mutation No A455E mutant or wt line Homozygous 1497 C 3 A polymorphism (no amino acid change) Weak wt 1898 ϩ 1 G 3 A line wt/E587A novel missense mutation or polymorphism Weak 1898 ϩ 1 G 3 A line wt/1898 ϩ 1 G 3 C-different mutation; G 3 C NOT G 3 A DISCUSSION The ACMG recommended panel of CF mutations has rapidly become the standard of care for US carrier screening. Login to comment
109 In fact, in our current assay an almost equal number of patients with positive mutant lines for the A455E mutation had sequence changes near the A455E locus as had true A455E mutations. Login to comment

PMID: 12592165 [PubMed] Navarro J et al: "[National program for neonatal screening for cystic fibrosis: implementation and preliminary results]."

No. Sentence Comment

46 3 Les mutations étudiées sont : 1717-1G > A - G542X - W 1282 X - N 1303 K - DF 508 (M) - 3849 + 10kbC > T - 621+1 G > T - R553X - G 551D, R117H, R1162X - R 334W - A455E - 2183 AA > G - 3659delC-- 1078 delT - D1507 - R347P - S 1251N, E60X, 2789+5G > A - 394del T - G 85 E - 1811+1.6 - Y122X - 711+1G > T - W 846 X - Y 1092 - 3272-26A > G. Login to comment

PMID: 12630958 [PubMed] Devaney J et al: "Cystic fibrosis mutation frequencies in an Irish population."

No. Sentence Comment

18 In a selected cohort of 40 patients, six other common ABCC7 mutations were screened for, using PCR-REA: R347P, A455E, R1162X, 384910kbC> T, W1282X and N1303K. Login to comment
27 Samples (n 40) were screened using an in-house optimized protocol to screen for six additional mutations (R347P, A455E, R1162X, 3849 10kbC > T, W1282X and N1303K). Login to comment

PMID: 12680831 [PubMed] Cimmino M et al: "Clinical characteristics and genotype analysis of patients with cystic fibrosis and nasal polyposis."

No. Sentence Comment

19 R117H and A455E also are considered to be `mild' mutations: they are associated with better lung function.18 Moss and King11 reported that DF508 homozygosity was found more frequently in the patients undergoing sinus surgery (58%) than in a control population (48%). Login to comment
47 Analysis of mutations in the CFTR gene as tested by the multiplex polymerase chain reaction (PCR), followed by the reverse dot-blot technique, which searches for 29 of the most frequent mutations (DF508, N1303K, G542X, W1282X, 1717±1 G-A, R553X, 2183 AA-G, DI507, G551D, R560T, 3849 10kbC > T, R1162X, 3659delC, 3905insT, G85E, 621 1GT, R117H, R347P, R334W, A455E, 2789 5GA, Q552X, S1251N, 3905insT, 394delTT, E60X, 2143delT, 2184delA, 711 5G > A), and by ASO dot-blot for the following mutations: I148T, R1158X, 4016 1T, G1244E G >A.26 Statistical analysis was performed using multivariate analysis, by forward stepwise comparison; it was done to ®nd out which of the examined characteristics could be associated (P < 0.01) to nasal polyposis. Login to comment

PMID: 12732620 [PubMed] Pagani F et al: "Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9."

No. Sentence Comment

83 Four of the natural substitutions, C31T (Q414X), G61A (G424S), T122G (I444S), and C155A (A455E), significantly decreased exon 9 inclusion to 48, 30, 40, and 16%, respectively, whereas only a modest decrease was evident for N418S. Login to comment
137 Identification of Regulatory Elements of Splicing in CFTR Exon 9-Three natural missense mutations with completely different effects on splicing (Q452P (A146C), which induces exon inclusion; A455E (C155A), causing exon exclusion; and V456F (G157T), with no effect) are located within 15 nucleotides. Login to comment
198 The natural mutations Q456P, A455E, and V456F correspond to A146C, C155A and G157T, respectively. Login to comment
221 WT sequence position AA change Nucleotide mutants Exon 9ϩ SR protein matrices above thresholds Disruption of preexisting sites New sites created by the mutations SC35 SR40 SF2 SR55 % WT 65 A 15 C 65 T 16 ⌬ 96 T 18 G 95 3.38 (13) G 19 A 52 A 20 G 80 C 31 Q414X T 50 A 43 G 62 SR40 0.28 (41) A 44 N414S G 59 46t49t 67 SR40 1.43 (41) G 61 G424S A 31 C 58 66g67a69g 68 SR40-1.01 (66) 3.21 (63) 2.24 (64) C 72 G 18 2.20 (67) A 63 2.01 (69) G 118 D443Y T 68 A 65 120g122a123g 96 2.24 (118) T 122 I444S G 40 A 144 G 55 T 40 C 145 G 85 A 87 A 146 G 92 3.02 (146) 2.66 (141) T 94 3.23 (143) Q452P C 96 3.46 (143) ⌬ 97 2.81 (142) 3.03 (141) G 147 T 97 C 98 2.70 (142) 3.00 (144) 2.53 (143) T 148 G 26 2.99 (142) 4.05 (143) C 90 2.49 (143) 2.47 (145) A 93 3.46 (145) T 149 C 82 2.99 (144) 3.53 (145) G 150 A 50 3.38 (148) C 62 T 151 A 65 C 67 3.00 (146) 3.15 (148) G 153 C 65 T 42 2.76 (153) G 154 T 18 C 20 C 155 A455E A 15 1.98 (152) G 3 T 5 G 156 T 10 3.59 (153) C 40 3.82 (153) G 157 V456F T 65 G 164ϩ ins 14 regulatory sequences derived from SR-specific score matrices, and the creation of novel enhancer and silencer controlling elements. Login to comment
282 For example, it appears that A455E can achieve adequate levels of chloride conduction at the cell surface (46, 47), causing only a partial CFTR protein processing defect (48). Login to comment
284 Furthermore, the modulation by the concentration of splicing factors, which have an inhibitory effect on the CFTR exon 9 (26, 49) and a specific and possibly individual variation distribution, can provide an explanation for the phenotypic and tissue-specific variability in CF patients, particularly in those carrying the A455E substitution. Login to comment

PMID: 12794695 [PubMed] Timmreck LS et al: "Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina."

No. Sentence Comment

82 CFTR Gene Mutations Tested DF508 R334W Y1092X 5T variant Y122X R347H G542X S549R 3,849 þ 4 G551D 3,849 þ 10 kb 2,789 þ 5 W1282X R553X 711 þ 1 3,905 þ T 621 þ 1 1,898 þ 1 N1303K 1,717À1 R1162X R117H 1078dT A455E D1507 Q493X 218dA R347P V520F G85E R560T S549N 3659dC Wolffian duct must occur at a time when the Mu¨llerian duct is no longer dependent on the Wolffian duct for development. Login to comment

PMID: 12865275 [PubMed] Ahmed N et al: "Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas."

No. Sentence Comment

294 Less common mutations included G85E and 5T (n=5 chromosomes), A455E and R1162X (n=4 chromosomes), R347, Y1092X, R334W, and V520F (n=3 chromosomes). Login to comment

PMID: 12881448 [PubMed] Malehorn DE et al: "Detection of cystic fibrosis mutations by peptide mass signature genotyping."

No. Sentence Comment

138 ⌬b 3 R Y 9863.78 G85E SerϾPhe 9923.90 Y 60.12 4.1 R N 7047.69 R117H AlaϾVal 7075.76 N 28.07 4.2 R Y 11161.32 lI48T AsnϾSer 11134.32 Y -27.00 621ϩ1 GϾT TyrϾTAA 6513.09 N -4648.23 5 R Y 11081.45 711ϩ1 GϾT ThrϾAsn 11094.48 Y 13.03 7.1 R N 7383.08 1078⌬T frameshift 9201.10 Y 1818.02 7 R Y 12233.9 R334W ArgϾGln 12205.87 Y -28.03 R347P ArgϾGly 12134.79 Y -99.11 9 F Y 14049.68 A455E AlaϾGlu 14107.74 Y 58.06 10.2 R Y 10525.57 ⌬I507 ⌬ Asp 10410.50 Y -115.07 ⌬F508 ⌬ Asp & LysϾAsn 10396.43 Y -129.14 11.2 F Y 11173.32 1717-1 GϾA GlyϾArg 11272.46 Y 99.14 G542X TrpϾLeu 11100.27 Y -73.05 G551D no change 11173.32 Y 0.00 R553X ThrϾMet 11203.42 Y 30.10 R560T no change 11173.32 Y 0.00 11 F N 8465.27 1717-1 GϾA no change 8465.27 N 0.00 G542X GlyϾTGA 6584.17 N -1881.10 G551D GlyϾAsp 8523.33 N 58.06 R553X ArgϾTGA 7541.18 N -924.09 R560T ArgϾThr 8410.21 N -55.06 12 F Y 10372.51 1898ϩ1 GϾA GlyϾAsp 10430.57 Y 58.06 13.2A R Y 10103.23 2184⌬A frameshift 8726.91 N -1376.32 14B R Y 9291.17 2789ϩ5 GϾA LeuϾPhe 9325.21 Y 34.04 16 F N 9398.67 3120ϩ1 GϾA ValϾIle 9412.72 N 14.05 19 F Y 17455.96 R1162X ArgϾTGA 6280.13 N -11175.83 3659⌬C frameshift 9650.06 N -7805.90 19i F Y 9699.9 3849ϩ10kB CϾT ArgϾTGA 7131.04 N -2568.86 20 F N 11125.48 W1282X TrpϾTGA 9370.40 N -1755.08 21 F Y 11183.44 N1303K AsnϾLys 11197.54 Y 14.10 a Denotes the directionality of exonic sequence when expressed as peptide. Login to comment
181 The heterozygous mutations depicted are as follows: (A), exon 3 wt/G85E; (B), exon 4.1 wt/R117H; (C), exon 4.2 wt/I148T; (D), exon 4.2 wt/621 ؉ 1G>T; (E), exon 5 wt/711 ؉ 1G>T; (F), exon 7.1 wt/1078⌬T; (G), exon 7 wt/R334W; (H), exon 7 wt/R347P; (I), exon 9 wt/A455E; (J), exon 10.2 wt/⌬I507; (K), exon 10.2 wt/⌬F508; (L), exon 11.2 wt/1717-1G>A; (M), exon 11 wt/G542X; (N), exon 11 wt/G551D; (O), exon 11 wt/R553X; (P), exon 11 wt/R560T; (Q), exon 12 wt/1898 ؉ 1G>A; (R), exon 13.2A wt/2184⌬A; (S), exon 14B wt/2789 ؉ 5G>A; (T), exon 16 wt/3120 ؉ 1G>A; (U), exon 19 wt/R1162X; (V), exon 19 wt/3659⌬C; (W), intron 19 wt/3849 ؉ 10kbC>T; (X), exon 20 wt/W1282X; (Y), exon 21 wt/N1303K. typical yield of purified protein was 1-30 ␮g/test well, depending on the analyte species. Login to comment

PMID: 12906319 [PubMed] Wallis C et al: "Atypical cystic fibrosis--diagnostic and management dilemmas."

No. Sentence Comment

110 This 5T variant reduces the splicing efficiency with lower levels of functioning CFTR and thus greater clinical impact.27 The A455E mutation is mostly associated with mild pancreatic disease. Login to comment

PMID: 12939655 [PubMed] Perri F et al: "Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the serine protease inhibitor, Kazal type 1 (SPINK1) gene in patients with alcoholic chronic pancreatitis."

No. Sentence Comment

33 Mutation screening of the CFTR gene The 31 most frequent mutations (F508del, I507del, G551D, G542X, N1303K, 1717-1G4A, W1282X, R553X, R347P, R347H, R334W, 3849+10kb C4T, R117H, 621+1G4T, A455E, S549N, R560T, S549R, V520F, Q493X, 3849+ 4A4G, 1078delT, R1162X, 3659delC, 3905insT, Y122X, 2183delAA4G, 2789+5G4A, 1898+1G4A, 711+1G4T, and G85E) were examined with the polymerase chain reaction (PCR) followed by an oligonucleotide ligation assay (OLA, Applied Biosystems, Foster City, CA, USA) and finally a sequence-coded separation. Login to comment

PMID: 12940920 [PubMed] Rowntree RK et al: "The phenotypic consequences of CFTR mutations."

No. Sentence Comment

170 Another example of correlation between a CFTR allele and pulmonary disease is the A455E mutation, which was associated with milder lung and pancreatic disease in A455E compound heterozygotes than F508 homozygotes in Quebec (De Braekeleer et al. 1997). Login to comment

PMID: 14576497 [PubMed] Pezzilli R et al: "Mutations of the CFTR gene in pancreatic disease."

No. Sentence Comment

59 The 29 Mutations and the Tn Polymorphism Which Can Be Detected by INNO-LiPA Assays Mutation Exon/Intron (i) E60X, G85E, 394delTT 3 621 + 1G > T, R117H (i) 4, 4 711 + 5G > A (i) 5 1078delT, R347P, R334W 7 A455E, Tn (i) 8, 9 ⌬F508, ⌬I507 10 G542X, 1717-1 G > A, G551D, R553X, R560T, Q552X (i) 10, 11 2183AA > G, 2184del A, 2143delT 13 2789 + 5G > A (i) 14b R1162X, 3659delC 19 3849 + 10kbC > T (i) 19 3905insT, W1282X, S1251N 20 N1303K 21 Group 3: pancreatic cancer CFTR gene mutations were identified only in 1 of the 18 patients (5.6%) with this cancer. Login to comment

PMID: 14605249 [PubMed] Derichs N et al: "Cystic fibrosis transmembrane conductance regulator (CFTR)-mediated residual chloride secretion does not protect against early chronic Pseudomonas aeruginosa infection in F508del homozygous cystic fibrosis patients."

No. Sentence Comment

9 CFTR mutations such as A455E have been reported to give rise to residual Cl-secretion and a milder disease phenotype, i.e. pancreatic sufficiency and less frequent PA colonization (2, 3). Login to comment
10 However, mildly diseased A455E heterozygous patients have been described who do not exhibit residual Cl-secretion (4). Login to comment

PMID: 14641997 [PubMed] Raskin S et al: "High allelic heterogeneity between Afro-Brazilians and Euro-Brazilians impacts cystic fibrosis genetic testing."

No. Sentence Comment

63 FREQUENCIES OF 70 CFTR MUTATIONS IN DIFFERENT STATES OF BRAZIL, BY CONTINENTA L GROUP CFTR mutations SC PR MG detected n n n n % n % N % DF508 53 39 54 146 47.1 8 10.5 154 39.9 G542X 6 9 8 23 7.4 1 1.3 24 6.2 R1162X 9 2 4 15 4.8 2 2.6 17 4.4 N1303K 5 5 0 10 3.2 0 0 10 2.6 R334W 5 1 4 10 3.2 0 0 10 2.6 G85E 2 2 4 8 2.6 1 1.3 9 2.3 1717-1G®A 1 3 2 6 1.9 0 0 6 1.6 W1282X 4 1 1 6 1.9 0 0 6 1.6 3849110kbC®T 1 3 1 5 1.6 0 0 5 1.3 R553X 0 2 0 2 0.7 0 0 2 0.5 1812-1G®A 0 1 3 4 1.3 1 1.3 5 1.3 2183AA®G 2 1 0 3 1.0 0 0 3 0.8 312011G®A 0 0 2 2 0.7 2 2.6 4 1.0 Y1092X 0 1 1 2 0.7 1 1.3 3 0.8 G551D 0 0 0 0 0 0 0 0 0 W1089X 0 0 1 1 0.3 0 0 1 0.3 6211G®T 0 1 0 1 0.3 0 0 1 0.3 Q1238X 0 1 0 1 0.3 0 0 1 0.3 711-1G®T 0 1 0 1 0.3 0 0 1 0.3 R347P 1 0 0 1 0.3 0 0 1 0.3 189811G®A 1 0 0 1 0.3 0 0 1 0.3 I507 0 0 1 1 0.3 0 0 1 0.3 Subtotal 91 73 86 250 80.7 16 21.1 266 68.9 Alleles with CFTR 5 27 28 60 19.4 60 79.0 120 31.1 mutations not detected Total 96 100 114 310 100.0 76 100.0 386 100.0 Detection rate (%) 94.8 73.0 75.4 250 80.7 16 21.1 266 68.9 The following 70 CFTR mutations were selected and tested on the basis of frequency in various populations, known association with CF, or predicted deleterious effect on the CFTR protein product; DF508, G542X, N1303K, G551D, R553X, DI507, A455E, A559T, C524X, D1270N, E60X, G178R, G330X, G85E, 2307insA, I148T, K710X, P574H, Q1238X, Q493X, Q890X, R1158X, R1162X, R117H, R334W, R347H, R347P 2307insA, I148T, K710X, P574H, Q1238X, Q493X, Q890X, R1158X, R1162X, R117H, R334W, R347H, R347P 2307insA, 1148T, K710X, P574H, Q1238X, Q493X, Q890X, R1158X, R1162X, R117H, R334W, R347H, R347P, R352Q, R560T, S1196X, S1255X, S364P, S549N, S549R, V520F, W1089X, W1282X, W1310X, W1316X, Y1092X, Y122X, Y563D, 1078delT,1677delTA,1717-1G-A,1812-1G-A,1898 1 1G-A, 2043delG,2183delAA-G, 2184delA, 2789 1 5G-A, 2869insG, 2909delT, 3120 1 1G-A, 3120G-A, 3358delAC, 3659delC, 3662delA, 3750delAG, 3791delC, 3821delT, 3849 1 10KbC-T, 3849 1 4A-G, 3905insT, 405 1 1G-A, 444delA, 556delA, 574delA, 621 1 1G-T, and 711 1 1G-T. aSC, Santa Catarina State; PR, Parana State; MG, Minas Gerais State; n, number of chromosomes. Login to comment

PMID: 14662004 [PubMed] Zeitlin PL et al: "Emerging drug treatments for cystic fibrosis."

No. Sentence Comment

66 Examples of Class 5 mutations include 3849 + 10 kB C→T, A455E or 2789 + 5 G→A. Login to comment
88 Class of mutation Molecular mechanism Pancreatic status (if known) Examples 1 No CFTR protein synthesis PI W1282X, G542X, R553X, 621 + 1 G→T, 1717-1 G→A, 3905insT, 394delTT 2 Abnormal CFTR processing and trafficking PI ∆F508, N1303K, P574H 3 Defective CFTR regulation (normal trafficking) PI G551D, G551S, G1349D, S1255P 4 Decreased CFTR chloride conductance PS R117H, R334W, R347P, P547H 5 Reduced synthesis and trafficking of normal CFTR PS A455E, 3849 + 10kb C→T, (5T) 6A Reduced apical stability PI S1455X, Q1412S, 4326delTC, 4279insA 6B Defective regulation of other ion channels PI G551D Note that the G551D is placed in Class 3 for defective regulation and Class 6B for defective regulation of the outwardly rectifying chloride channel. Login to comment

PMID: 14685259 [PubMed] Lewis HA et al: "Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

216 CF mutations in NBD1 The majority of sites of CF-causing missense mutations occur in NBD1, primarily in its a-subdomain, and the locations in the mNBD1 structure of the most common of these (A455E, G480C, I506T, DI507, DF508, S549N, S549R, G551D, A559T, R560T, Y569D, and D648V; Bobadilla et al, 2002) are shown in Figure 3D. Login to comment

PMID: 14731137 [PubMed] Gaskin KJ et al: "CFTR gene and cystic fibrosis."

No. Sentence Comment

7 In contrast, patients with at least one copy of type IV and V mutations, for example R117H or A455E, usually have sufficient preservation of their exocrine pancreatic function to prevent malabsorption and are classified as pancreatic sufficient. Login to comment

PMID: 14739679 [PubMed] Farriaux JP et al: "Neonatal screening for cystic fibrosis: France rises to the challenge."

No. Sentence Comment

114 In its present version, the kit allows screening for 20 CFTR gene mutations (F508del, G542X, N1303K, 1717-1G>A, G551D, W1282X, R553X, I507del, 1078delT, 2183AA>G, 3849 þ 10kbC>T, R1162X, 621 þ 1G>T, R334W, R347P, 3659delC, R117H, S1251N, E60X, A455E) in one workday; moreover, it does not require any speci'c equipment. Login to comment

PMID: 14747162 [PubMed] Wu CC et al: "Cystic fibrosis transmembrane conductance regulator gene screening and clinical correlation in Taiwanese males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

42 Screening by an INNO-LiPA CFTR17+Tn kit For further con®rmation, we used a commercial kit (INNO-LiPA CFTR17+Tn; Innogenetics, Ghent, Belgium) that allowed the detection of 17 mutations (including 394delTT, G85E, E60X, 621+1G®T, R117H, 711+5G®A, 1078delT, R347P, R334W, A455E, 2143delT, 2183AA®G, 2184delA, 2789+5G®A, R1162X, 3659delC and 3849+10kbC®T) associated with IVS8-Tn polymorphisms (5T/7T/9T) in the CFTR gene to analyse our 27 patients and 46 normal, fertile control males. Login to comment

PMID: 14998948 [PubMed] Danziger KL et al: "Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis."

No. Sentence Comment

59 Polyacrylamide gels were analysed for the presence of mutations following staining in ethidium bromide (EtBr) and image capture under UV using the Gel Doc 1000 system Table I. List of CFTR mutations included in common mutation panels American College of Medical Genetics CF panel (25 mutations) DF508 G542X G551D R117H W1282X N1303K R1162X 3849+10kbC®T DI507 R553X 1717-1G®A 621+1G®T R560T 3659delC 3120+1G®A I148T G85E R334W A455E 1898+1G®A 2148delA 711+1G®T 2789+5G®A R347P 1078delT Six additional mutations and one polymorphism in UCSF panel (31 mutations) Y1092X R347H 3849+4 Q493X 3905insT S549N F508C (polymorphism) (BioRad). Login to comment

PMID: 15010427 [PubMed] Strom CM et al: "Direct visualization of cystic fibrosis transmembrane regulator mutations in the clinical laboratory setting."

No. Sentence Comment

178 The optimal spotting conditions for each probe are indicated by the boxes around spots in C. wild-type controls and heterozygotes for each ACMG mutation and polymorphism, DNA from 12 compound heterozygotes (⌬F508/1898 ϩ 1GϾA, 711 ϩ 1GϾT/⌬F508, G85E/621 ϩ 1GϾT, 3659delC/⌬F508, 3120 ϩ 1GϾA/ 621 ϩ 1GϾT, R347P/G551D, A455E/⌬F508, R560T/ dF508, R553X/⌬F508, 621 ϩ 1GϾT/⌬F508, 621 ϩ 1GϾT/ 711 ϩ 1GϾT, R117H/⌬F508, and I506V/⌬F508) and DNA from 4 homozygous patients (⌬F508 and 2789 ϩ 5GϾA, 3849 ϩ 10kbCϾT, and G542X) was used in validation experiments. Login to comment
199 In this series, there were 17 ⌬F508 heterozygous patient samples, 1 ⌬F508 homozygous sample, 2 R117H heterozygous samples, and 1 heterozygous patient sample each for I148T, G542X, R553X, R347P, and 2789 ϩ 5GϾA, for a total of 26 mutant alleles. Additional mutant alleles detected in the control samples included three fixed control samples (⌬F508 homozygous, 5T/WT, 3659delC/⌬F508) on every plate and two heterozygous samples (R560T and 1078delT) and one heterozygous sample each for R334W, A455E, R347P, R117H, ⌬I507, I507V, G551D, and 1717-1GϾA as rotating controls. Login to comment

PMID: 15047968 [PubMed] King PT et al: "Role of CFTR mutations in adult bronchiectasis."

No. Sentence Comment

230 The patients were screened for the 10 most common mutations in the local population (DF508, D1507, V520F, G542X, G551D, R553X, R117H, 621+1GRT, A455E and N1303K) responsible for 82% of cases of CF and the 5T mutation by previously published methods.7 8 Ethical approval for the project was obtained from the ethics committee at MMC. Login to comment

PMID: 15084988 [PubMed] Naruse S et al: "A finger sweat chloride test for the detection of a high-risk group of chronic pancreatitis."

No. Sentence Comment

50 The DNA samples were analyzed using an amplification refractory mutation system kit for 20 common major CFTR mutations (E60X, R117H, R334W, R347P, A455E, ⌬I507, ⌬F508, G542X, G551D, R553X, 621+1G>T, 1078delT, R1162X, S1251N, W1282X, N1303K, 1717-1G>A, 2183AA>G, 3659delC, 3849+10kbC>T) (Elucigene CF 20, AstraZeneca Diagnostics, Abingdon, UK) following the standard procedures recommended by the manufacturer. Login to comment

PMID: 15121783 [PubMed] Fujiki K et al: "Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis."

No. Sentence Comment

218 The 20 most common CF mutations (E60X, R117H, R334W, R347P, A455E, DI507, DF508, G542X, G551D, R553X, 621+1GRT, 1078delT, R1162X, S1251N, W1282X, N1303K, 1717-1GRA, 2183AARG, 3659delC, and 3849+10kbCRT) were tested by an Elucigene CF20 kit (AstraZeneca Diagnostics, Abingdon, Oxfordshire, UK). Login to comment

PMID: 15141088 [PubMed] Cormet-Boyaka E et al: "Rescuing cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by transcomplementation."

No. Sentence Comment

128 To gauge the potential physiologic significance of this transcomplementation effect, we compared the transport activity and the amount of mature ⌬F508-CFTR protein that could be induced by transcomplementation to that observed for a partial processing mutant that associates with mild CF (A455E) (21). Login to comment
129 Although the transport activity and the amount of mature protein for the rescued ⌬F508-CFTR was considerably less than that observed for wild-type CFTR, both parameters were similar to that detected for the A455E mutant (Fig. 3 C and D). Login to comment
130 The A455E mutant associates with a mild phenotype presumably because it retains partial function [it has been reported that only 5-10% of ''normal`` CFTR activity is required to prevent severe disease (22, 23)]. Login to comment
160 (C) Rescued ⌬F508-CFTR exhibits macroscopic transport activity comparable to that of A455E-CFTR, a partial processing mutant associated with mild disease. Login to comment
163 (Inset) Enlarged view of the permeability responses of cells transfected with A455E () or cotransfectedwithfragment1-633and⌬F508-CFTR(ƒ)tothecAMPmixture. Login to comment
164 (D) Biochemical analysis of the band C forms of transcomplemented ⌬F508-CFTR and A455E-CFTRintransfectedCOS-7cells.Cellswereanalyzedforproteinexpression 48 h after transfection as described in Methods. Login to comment

PMID: 15173476 [PubMed] Comeau AM et al: "Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections."

No. Sentence Comment

79 The 16-mutation panel included ⌬F508, R117H, G551D, G542X, W1282X, N1303K, R334W, 621 ϩ 1GϾT, R553X, ⌬I507, 1717-1GϾA, R347P, R560T, 3849 ϩ 10kbCϾT, A455E, and S549N. Login to comment
159 Genotypes and Frequencies Observed in 112 CF-Affected Infants First Mutation Second Mutation N ⌬F508 ⌬F508 55 ⌬F508 R117H 7* ⌬F508 G551D 4 ⌬F508 N1303K 3 ⌬F508 W1282X 3 ⌬F508 G542X 2 ⌬F508 1898 ϩ 1 G Ͼ A 2 G85E R117C 2 ⌬F508 1717-GϾA 1 ⌬F508 3849 ϩ 10kbC Ͼ T 1 ⌬F508 R1066C 1 ⌬F508 Y1092X 1 ⌬F508 L206W 1 ⌬F508 R560T 1 ⌬F508 1152H 1 ⌬F508 621 ϩ 1G Ͼ T 1 R117H G551D 1 R117H G85E 1 G551D 2789 ϩ 5GϾA 1 G551D R117C 1 G85E 711 ϩ 1GϾT 1 W1282X 3849 ϩ 10kbCϾT 1 R553X 2183AAϾG 1 A455E S549R 1 ⌬F508 Unknown† 13 N1303K Unknown 2 G542X Unknown 1 Unknown Unknown 2 * Includes 1 of the false-negative screens. Login to comment

PMID: 15176679 [PubMed] Decaestecker K et al: "Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic fibrosis patients."

No. Sentence Comment

138 In patients carrying mutations such as R117H, A455E, R334W and 3849z10 kb CwT, which are reported to correlate with a milder phenotype, 40-87% have PS [21, 27]. Login to comment

PMID: 15233679 [PubMed] Choudari CP et al: "Risk of pancreatitis with mutation of the cystic fibrosis gene."

No. Sentence Comment

130 In a study of more than 500 CF patients, five mutations (R117H, R334W, R347P, A455E, and P574H) were found exclusively in pancreatic sufficient patients (8). Login to comment

PMID: 15238770 [PubMed] Felley C et al: "The role of CFTR and SPINK-1 mutations in pancreatic disorders in HIV-positive patients: a case-control study."

No. Sentence Comment

42 Samples were tested: (i) for 20 common CFTR mutations (delF508, 621+1G.T, G542X, 3849+10kbC.T, N1303K, 3659delC, 1717-1G.A, 1078delT, W1282X, R347P, G551D, A455E, R553X, S1251N, R1162X, delF507, R334W, 2183AA.G, R117H, and E60X; Elucigene CF20; Orchid Biosciences, Abingdon, UK); (ii) for the CFTR IVS8 5T variant (Elucigene CF Poly-T; Orchid); and (iii) for the SPINK-1 N34S polymorphism, by poly- Copyright (c) Lippincott Williams & Wilkins. Login to comment

PMID: 15274098 [PubMed] Davis PB et al: "Relation of sweat chloride concentration to severity of lung disease in cystic fibrosis."

No. Sentence Comment

26 T (12); A455E (1); D1270N; G85E (3); R117H (4); R334W (1); R347H (1); T347P (6); 2859 þ 5 G ! Login to comment

PMID: 15343184 [PubMed] Borowitz D et al: "Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis."

No. Sentence Comment

116 FE-1 values in subjects with CFTR mutations associated with pancreatic sufficiency11 N Mean (mg/g stool) Median (mg/g stool) Range (mg/g stool) Subjects with at least one PS allele* FE-1 >200 mg/g stool 16 584 582.9 349-773 FE-1 <200 mg/g stool 5 64.4 74.8 0-125 Subjects with at least one PS variable alleley FE-1>200 mg/g stool 29 496.2 493.6 224-798 FE-1 <200 mg/g stool 13 76.1 65.9 0-187 *Pancreatic sufficient dominant CF alleles G551S R117H R347H P574H R334W R352Q T3381 yVariable pancreatic sufficient CF mutations G85E 3849 + 10 kb C fi T R347P 2789 + 5G fi A A455E In summary, FE-1 is an accurate, easily obtained screening test to classify patients with CF as PI or PS. Login to comment

PMID: 15354331 [PubMed] Strom CM et al: "Cystic fibrosis screening: lessons learned from the first 320,000 patients."

No. Sentence Comment

47 Frequency, all tests Frequency, CF mutations (%) delta F508 7610 1:44 75% R117H/7T or 9T 1030 1:325 NAb R117H/5T 103 1:3,254 0.51c W1282X 529 1:625 5.2 G542X 382 1:909 3.8 G551D 278 1:1,250 2.7 N1303K 201 1:1,668 2.0 3849ϩ10kb CϾT 167 1:2,007 1.6 1717-1 GϾA 102 1:3,286 1.0 R553X 102 1:3,286 1.0 621ϩ1 GϾT 98 1:3,420 0.97 2789ϩ5 GϾA 82 1:4,087 0.80 3120ϩ1 GϾA 73 1:4,591 0.72 R1162X 54 1:6,207 0.53 R334W 54 1:6,207 0.53 685E 52 1:6,446 0.51 R560T 52 1:6,446 0.51 Delta I507 51 1:6,572 0.50 711ϩ1 GϾT 40 1:8,380 0.39 1898ϩ1 GϾA 37 1:9,059 0.36 3659 del C 36 1:9,311 0.36 A455E 34 1:9,858 0.33 R347P 33 1:10,158 0.32 2184 del A 14 1:23,943 0.14 1078 del T 6 1:55,867 0.06 a I148T has been eliminated from these data. Login to comment

PMID: 15371902 [PubMed] Watson MS et al: "Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel."

No. Sentence Comment

70 It has been ar- Table 1 CFTR mutation frequency among individuals with clinically diagnosed cystic fibrosis by racial/ethnic group and in a pan-ethnic U.S. population CFTR mutation Mutation frequency among individuals with clinically diagnosed cystic fibrosis (%) Non-Hispanic Caucasian Hispanic Caucasian African American Asian American Ashkenazi Jewish Pan-Ethnic Population5 delF508 72.42 54.38 44.07 38.95 31.41 66.31 G542X 2.28 5.10 1.45 0.00 7.55 2.64 W1282X 1.50 0.63 0.24 0.00 45.92 2.20 G551D 2.25 0.56 1.21 3.15 0.22 1.93 621ϩ1GϾT 1.57 0.26 1.11 0.00 0.00 1.30 N1303K 1.27 1.66 0.35 0.76 2.78 1.27 R553X 0.87 2.81 2.32 0.76 0.00 1.21 dell507 0.88 0.68 1.87 0.00 0.22 0.90 3849ϩ10kbCϾT 0.58 1.57 0.17 5.31 4.77 0.85 3120ϩ1GϾT 0.08 0.16 9.57 0.00 0.10 0.86 R117H 0.70 0.11 0.06 0.00 0.00 0.54 1717-1GϾT 0.48 0.27 0.37 0.00 0.67 0.44 2789ϩ5GϾA 0.48 0.16 0.00 0.00 0.10 0.38 R347P 0.45 0.16 0.06 0.00 0.00 0.36 711ϩ1GϾT 0.43 0.23 0.00 0.00 0.10 0.35 R334W 0.14 1.78 0.49 0.00 0.00 0.37 R560T 0.38 0.00 0.17 0.00 0.00 0.30 R1162X 0.23 0.58 0.66 0.00 0.00 0.30 3569delC 0.34 0.13 0.06 0.00 0.00 0.28 A455E 0.34 0.05 0.00 0.00 0.00 0.26 G85E 0.29 0.23 0.12 0.00 0.00 0.26 2184delA 0.17 0.16 0.05 0.00 0.10 0.15 1898ϩ1GϾA 0.16 0.05 0.06 0.00 0.10 0.13 l148T 0.09 0.09 0.05 0.00 0.10 0.08 1078delT 0.02 0.09 0.00 0.00 0.00 0.03 Total 88.40 71.90 64.51 48.93 94.14 84.00 gued that a laboratory is obligated to report any and all information that is gleaned from a test system, however, there is no regulatory requirement and practice varies. Login to comment

PMID: 15371903 [PubMed] Sugarman EA et al: "CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations."

No. Sentence Comment

35 87 mutation panel The following mutations were included in the panel: ⌬F508, ⌬F311, ⌬I507, A455E, A559T, C524X, D1152H, D1270N, E60X, G178R, G330X, G480C, G542X, G551D, G85E, G91R, I148T, K710X, L206W, M1101K, N1303K, P574H, Q1238X, Q359K/T360K, Q493X, Q552X, Q890X, R1066C, R1158X, R1162X, R117C, R117H, R1283M, R334W, R347H, R347P, R352Q, R553X, R560T, S1196X, S1251N, S1255X, S364P, S549I, S549N, S549R, T338I, V520F, W1089X, W1282X, Y1092X, Y563D, 1078delT, 1161delC, 1609delCA, 1677delTA, 1717-1GϾA, 1812-1GϾA, 1898ϩ1GϾA, 1898ϩ5GϾT, 1949del84, 2043delG, 2143delT, 2183delAAϾG, 2184delA, 2307insA, 2789ϩ5GϾA, 2869insG, 3120ϩ1GϾA, 3120GϾA, 3659delC, 3662delA, 3791delC, 3821delT, 3849ϩ10kbCϾT, 3849ϩ4AϾG, 3905insT, 394delTT, 405ϩ1GϾA, 405ϩ3AϾC, 444delA, 574delA, 621ϩ1GϾT, 711ϩ1GϾT, 711ϩ5GϾA, 712-1GϾT, 3876delA CFTR mutation analysis Genomic DNA was extracted from peripheral blood lymphocytes, buccal cell swabs, or bloodspots by Qiagen QIAmp 96 DNA Blood Kit. Specimens were tested for 87 mutations by a pooled allele-specific oligonucleotide (ASO) hybridization method as previously described.16,17 Two multiplex chain reactions (PCR) were used to amplify 19 regions of the CFTR gene. Login to comment

PMID: 15371905 [PubMed] Palomaki GE et al: "Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population."

No. Sentence Comment

32 Data from the International Cystic Fibrosis Consortium were taken from Table 1 of its publication.4 Data from the Cystic Fibrosis Foundation National Patient Registry were taken from the year 1999 and stratified according to whether or not the patient was seen Table 1 CFTR mutation frequencies among Hispanic Caucasians with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) CF Consortiumb CF Foundationc Average Cumulative 1 delF508 45.51 63.25 54.38 54.38 2 G542X 5.11 5.09 5.10 59.48 8 delI507 0.59 5.02 2.81 62.29 22 R334W 2.25 1.31 1.78 64.07 6 N1303K 1.65 1.67 1.66 65.73 10 3849 ϩ 10kbC Ͼ T 1.60 1.53 1.57 67.30 7 R553X 0.63 0.73 0.68 67.98 5 W1282X 0.53 0.73 0.63 68.61 19 R1162X 0.57 0.58 0.58 69.19 3 G551D 0.31 0.80 0.56 69.75 12 1717 - 1G Ͼ T 0.10 0.44 0.27 70.02 4 621 ϩ 1G Ͼ T 0.00 0.51 0.26 70.28 14 711 ϩ 1G Ͼ T 0.10 0.36 0.23 70.51 18 G85E 0.10 0.36 0.23 70.74 11 2789 ϩ 5G Ͼ A 0.10 0.22 0.16 70.90 13 R347P 0.10 0.22 0.16 71.06 20 2184delA 0.10 0.22 0.16 71.22 24 3120 ϩ 1G Ͼ T 0.10 0.22 0.16 71.38 17 3569delC 0.10 0.15 0.13 71.51 9 R117H 0.00 0.22 0.11 71.62 23 I148T 0.10 0.07 0.09 71.71 25 1078delT 0.10 0.07 0.09 71.80 16 A455E 0.10 0.00 0.05 71.85 21 1898 ϩ 1G Ͼ A 0.10 0.00 0.05 71.90 15 R560T 0.00 0.00 0.00 71.90 All 25 59.95 83.77 71.90 a The order is based on that found for non-Hispanic Caucasians.3 b Based on between 178 and 958 chromosomes (International Cystic Fibrosis Genetic Analysis Consortium.4 c Based on 1374 chromosomes from clinically diagnosed persons registered in the Cystic Fibrosis Foundation National Patient Registry. Login to comment
54 Only three mutations were never identified (R560T, A455E, and 1898ϩ1GϾA). Login to comment
80 The larger data- Table 2 CFTR mutation frequencies among African American individuals with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) CF Consortiumb CF Foundationc Average Cumulative 1 delF508 35.50 52.63 44.07 44.07 24 3120 ϩ 1G Ͼ T 12.50 6.64 9.57 53.64 8 delI507 0.74 3.89 2.32 55.96 7 R553X 2.37 1.37 1.87 57.83 2 G542X 1.18 1.72 1.45 59.28 3 G551D 0.59 1.83 1.21 60.49 4 621 ϩ 1G Ͼ T 1.18 1.03 1.11 61.60 19 R1162X 0.74 0.57 0.66 62.26 22 R334W 0.74 0.23 0.49 62.75 12 1717 - 1G Ͼ T 0.74 0.00 0.37 63.12 6 N1303K 0.00 0.69 0.35 63.47 5 W1282X 0.00 0.47 0.24 63.71 10 3849 ϩ 10kbC Ͼ T 0.00 0.34 0.17 63.88 15 R560T 0.00 0.34 0.17 64.05 18 G85E 0.00 0.23 0.12 64.17 9 R117H 0.00 0.11 0.06 64.23 13 R347P 0.00 0.11 0.06 64.29 17 3569delC 0.00 0.11 0.06 64.35 21 1898 ϩ 1G Ͼ A 0.00 0.11 0.06 64.41 20 2184delA 0.10 0.00 0.05 64.46 23 I148T 0.10 0.00 0.05 64.51 11 2789 ϩ 5G Ͼ A 0.00 0.00 0.00 64.51 14 711 ϩ 1G Ͼ T 0.00 0.00 0.00 64.51 16 A455E 0.00 0.00 0.00 64.51 25 1078delT 0.00 0.00 0.00 64.51 All 25 56.46 72.42 64.51 a The order is based on that found for non-Hispanic Caucasians.3 b Based on between 79 and 169 chromosomes reported by the International Cystic Fibrosis Genetic Analysis Consortium.4 c Based on 874 chromosomes from clinically diagnosed persons registered in the Cystic Fibrosis Foundation National Patient Registry. Login to comment
107 An earlier article10 reported that 97% of mutations were identified in 90 chromosomes from Ashkenazi Jewish individ- Table 3 CFTR mutation frequencies among Ashkenazi Jewish Caucasian individuals with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) CF Consortiumb Cumulative 5 W1282X 45.92 45.92 1 delF508 31.41 77.33 2 G542X 7.55 84.88 10 3849 ϩ 10kbC Ͼ T 4.77 89.65 6 N1303K 2.78 92.43 12 1717 - 1G Ͼ T 0.67 93.10 7 R553X 0.22 93.32 3 G551D 0.22 93.54 24 3120 ϩ 1G Ͼ T 0.10 93.64 21 1898 ϩ 1G Ͼ A 0.10 93.74 20 2184delA 0.10 93.84 23 I148T 0.10 93.94 11 2789 ϩ 5G Ͼ A 0.10 94.04 14 711 ϩ 1G Ͼ T 0.10 94.14 8 delI507 0.00 94.14 19 R1162X 0.00 94.14 22 R334W 0.00 94.14 4 621 ϩ 1G Ͼ T 0.00 94.14 15 R560T 0.00 94.14 18 G85E 0.00 94.14 9 R117H 0.00 94.14 13 R347P 0.00 94.14 17 3569delC 0.00 94.14 16 A455E 0.00 94.14 25 1078delT 0.00 94.14 Sum 94.14 a The order is based on that found for non-Hispanic Caucasians.3 b Based on between 57 and 503 chromosomes reported by the International Cystic Fibrosis Genetic Analysis Consortium.4 uals with cystic fibrosis, using a panel of 11 mutations. Login to comment
115 In an- Table 4 CFTR mutation frequencies among Asian American individuals with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) Heim et al.1b CF Foundationc Average Cumulative 1 delF508 18.80 59.09 38.95 38.95 10 3849 ϩ 10kbC Ͼ T 0.00 10.61 5.31 44.26 3 G551D 6.30 0.00 3.15 47.41 6 N1303K 0.00 1.52 0.76 48.17 8 delI507 0.00 1.52 0.76 48.93 2 G542X 0.00 0.00 0.00 48.93 4 621 ϩ 1G Ͼ T 0.00 0.00 0.00 48.93 5 W1282X 0.00 0.00 0.00 48.93 7 R553X 0.00 0.00 0.00 48.93 9 R117H 0.00 0.00 0.00 48.93 11 2789 ϩ 5G Ͼ A 0.00 0.00 0.00 48.93 12 1717 - 1G Ͼ T 0.00 0.00 0.00 48.93 13 R347P 0.00 0.00 0.00 48.93 14 711 ϩ 1G Ͼ T 0.00 0.00 0.00 48.93 15 R560T 0.00 0.00 0.00 48.93 16 A455E 0.00 0.00 0.00 48.93 17 3569delC 0.00 0.00 0.00 48.93 18 G85E 0.00 0.00 0.00 48.93 19 R1162X 0.00 0.00 0.00 48.93 20 2184delA 0.00 0.00 0.00 48.93 21 1898 ϩ 1G Ͼ A 0.00 0.00 0.00 48.93 22 R334W 0.00 0.00 0.00 48.93 23 I148T 0.00 0.00 0.00 48.93 24 3120 ϩ 1G Ͼ T 0.00 0.00 0.00 48.93 25 1078delT 0.00 0.00 0.00 48.93 Sum 25.10 72.74 48.93 a The order is based on that found for non-Hispanic Caucasians.3 b Based on 20 chromosomes. Login to comment
173 For exam- Table 7 Estimated number of carriers of the 25 recommended CFTR mutations by racial/ethnic group and weighted average, representing the panethnic population in the United States for 2002 Order CFTR mutation Number of CFTR Mutation Carriers Panethnic frequency, % Non-Hispanic Caucasian Hispanic Caucasian African American Asian American Ashkenazi Jewish Total 1 delF508 64,779 8,207 4,272 886 796 78,940 66.31 2 G542X 2,039 770 141 0 191 3,141 2.64 5 W1282X 1,342 95 23 0 1,164 2,624 2.20 3 G551D 2,013 85 117 72 6 2,293 1.93 4 621 ϩ 1G Ͼ T 1,404 39 108 0 0 1,551 1.30 6 N1303K 1,136 251 34 17 70 1,508 1.27 7 R553X 778 424 225 17 0 1,444 1.21 8 delI507 787 103 181 0 6 1,077 0.90 10 3849 ϩ 10kbC Ͼ T 519 237 16 121 121 1,014 0.85 24 3120 ϩ 1G Ͼ T 72 24 928 0 3 1,027 0.86 9 R117H 626 17 6 0 0 649 0.55 12 1717 - 1G Ͼ T 429 41 36 0 17 523 0.44 11 2789 ϩ 5G Ͼ A 429 24 0 0 3 456 0.38 13 R347P 403 24 6 0 0 433 0.36 14 711 ϩ 1G Ͼ T 385 35 0 0 3 423 0.36 22 R334W 125 269 47 0 0 441 0.37 15 R560T 340 0 16 0 0 356 0.30 19 R1162X 206 88 64 0 0 358 0.30 17 3569delC 304 20 6 0 0 330 0.28 16 A455E 304 8 0 0 0 312 0.26 18 G85E 259 35 12 0 0 306 0.26 20 2184delA 152 24 5 0 3 184 0.15 21 1898 ϩ 1G Ͼ A 143 8 6 0 3 160 0.13 23 I148T 80 14 5 0 3 102 0.09 25 1078delT 18 14 0 0 0 32 0.03 All 79,072 10,856 6,193 1,113 2,389 99,684 84.00 Bolded numbers indicate mutations that are more likely to be found in a racial/ethnic group other than non-Hispanic Caucasians. Login to comment

PMID: 15371906 [PubMed] Kornreich R et al: "Premarital and prenatal screening for cystic fibrosis: experience in the Ashkenazi Jewish population."

No. Sentence Comment

62 The additional mutations that were detected were R117H (n ϭ 7), I148T (6), A455E (2), R334W (2), G551D (1), and R553X (1). Login to comment
86 For example, W1282X was the most prevalent mutation among Ashkenazi Jews, present in 46.4% of AJ carriers, whereas it was present in only 1.5% of non-Hispanic Caucasian CF patients.8 ⌬F508, the most common mutation in non-Hispanic Caucasian CF pa- Table 3 Frequency of CFTR mutations among screenees reporting 100% AJ or Ͻ 100% AJ descent who requested carrier testing for CF and at least one other AJ recessive disease CF mutation % of mutations in carriers reporting 100% AJ descent (n ϭ 45,530-117,145) % of mutations among carriers reporting Ͻ100% AJ descent (n ϭ 7,393) % of Non-Hispanic Caucasian CF patient chromosomes8 (n ϭ 37,263) W1282X 46.4 (n ϭ 117,136) 32.3 1.5 ⌬F508 27.1 (n ϭ 117,145) 35.7 71.5 D1152H 12.0 (n ϭ 44,530) 8.7 0.03 G542X 5.3 (n ϭ 117,140) 6.1 2.3 3849ϩ10kb CϾT 4.8 (n ϭ 117,135) 4.9 0.7 N1303K 3.8 (n ϭ 117,141) 3.0 1.3 1717-1GϾA 0.6 (n ϭ 60,191) 1.9 0.7 R117H a 2.7 0.8 I148T a 2.3 0.05 R334W - 0.76 0.16 A455E - 0.76 0.19 G551D a 0.38 2.5 R553X - 0.38 1.0 a These mutations were detected when screening Ϸ2,300 100% AJ individuals with the ACMG recommended panel. Login to comment

PMID: 15371908 [PubMed] Buyse IM et al: "Use of MALDI-TOF mass spectrometry in a 51-mutation test for cystic fibrosis: evidence that 3199del6 is a disease-causing mutation."

No. Sentence Comment

77 This assay also demonstrated heterozygosity for the G542X mutation, and reflex testing for the 5T variant at CFTR intron 8 showed a genotype of 7T/9T in this patient (data not Table 3 Description of the 16 multiplex assays designed to analyze 51 CFTR mutations Multiplex Mutations Exon 1 1078delT, G314E, R352Q, G330X 7 2 R347H, R347P, R334W, 1717-1A 7, 11 3 R553X, S549N, R1162X 11, 19 4 A559T, R560T, G551D 11 5 G542X, S549R, 621ϩ1T, Y122X 4, 11 6 W1282X, 3876delA, 3905insT, D1152H 18, 20 7 3849ϩ4G, 3659delC, 1898ϩ1A 12, 19 8 405ϩ1A, 405ϩ3C, 3120A, 3120ϩ1A 3, 16 9 394delTT, E60X, G85E 3 10 A455E, ⌬F508a 9, 10 11 G480C, Q493X, V520F 10 12 711ϩ1T, G178R, 3199del6 5, 17a 13 2143delT, 2184delA, K710X, F316L 7, 13 14 I148T, R117H, R117C 4 15 N1303K, 2789ϩ5A, 3849ϩ10kbT 14b, intron19, 21 16 ⌬I507a 10 17 5Tb intron 8 a F508C and I507V, I506V, I506M variants are tested for concurrently with the ⌬F508 and ⌬I507 assays respectively. Login to comment
93 Two previously unreported missense alleles were identified: G314A (allelic to G314E) and A455V (allelic to A455E). Login to comment

PMID: 15371909 [PubMed] Edelmann L et al: "Cystic fibrosis carrier screening: validation of a novel method using BeadChip technology."

No. Sentence Comment

35 Mutation controls included DNA from previously identified positive patient samples (I148T, D1152H, W1282X, R117H, G85E, A455E, delF508, N1303K) and DNA from NIGMS Human Genetic Cell Repositories (Coriell Cell Repositories) (delF508, delI507, G542X, R560T, 3849ϩ10kbCϾT, N1303K, G85E; G551D, R553X, 621ϩ1GϾT, 1717-1GϾA, A455E, R334W, R347P, R1162X, 3659delC; 711ϩ1GϾT, 2789ϩ5GϾA, 3120ϩ1GϾA). Login to comment
46 Mutant ASOs were end-labeled with ␥-32 P-ATP and pooled into three subgroups (IA-IC) for Group I and four subgroups (IIA-IID) for Group II mutations with the following breakdown of mutations: IA: delF508, delI507, W1282X, R117H; IB: G542X, R560T, 3849ϩ10kbCϾT, N1303K, G85E; IC: G551D, R553X, 621ϩ1GϾT, 1717-1GϾA, I148T; IIA: A455E, R334W, D1152H; IIB: R347P, 1078delT, R1162X, 3659delC; IIC: 711ϩ1GϾT, 1898ϩ1GϾA, 2789ϩ5GϾA, 3120ϩ1GϾA; IID: 2184delA. Login to comment

PMID: 15591474 [PubMed] Rodman DM et al: "Late diagnosis defines a unique population of long-term survivors of cystic fibrosis."

No. Sentence Comment

90 Type III-V mutations, typically A455E and other missense mutations, together with unknown mutations (likely rare missense mutations) were more common in the LD group (solid bar); p Ͻ 0.05 by Fisher`s exact test. LD group, four individuals lacked a ⌬F508 allele, and only one individual was homozygous. Login to comment
117 GENOTYPE DISTRIBUTION Early Diagnosis Late Diagnosis ⌬F508/⌬F508 10 1 ⌬F508/⌬I507 1 ⌬F508/G551D 1 ⌬F508/M1101K 1 ⌬F508/P67L/11027T 1 ⌬F508/3120G-A 1 ⌬F508/2789ϩ5G-A 1 2 ⌬F508/W1282X 1 ⌬F508/621ϩ1G-T 1 ⌬F508/R347P 1 ⌬F508/3849ϩ10kbC-T 1 1 ⌬F508/A455E 2 ⌬F508/R347H 2 ⌬F508/D1152H 1 ⌬508/I148T 1 ⌬F508/R117H 1 ⌬F508/Y109N 1 ⌬F508/IVS8-5T 1 ⌬F508/unknown 3 5 S1251N/D1152H 1 G542X/R117C 1 R117H/G551D 1 W1282X/D1152H 1 Unknown 4 4 Values represent number of individuals in each diagnostic group with each genotype. Login to comment

PMID: 15705292 [PubMed] Claustres M et al: "Molecular pathology of the CFTR locus in male infertility."

No. Sentence Comment

179 2789H-5G-*A. or the 5T allele) or inefficienl trafficking (A455E). Login to comment
466 inducing exon inclusion (Q452P) or exclusion (A455E). Login to comment
472 This is the case of missense A455E, which was found in this study to increase exon 9 skipping {50% in a TGIITO context). Login to comment

PMID: 15758625 [PubMed] Turcios NL et al: "Cystic fibrosis: an overview."

No. Sentence Comment

56 T R334W A455E R347H 2789 5G ! Login to comment

PMID: 15772171 [PubMed] De Boeck K et al: "Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype."

No. Sentence Comment

136 Class IV and V mutations reported among the patients with PI included D1152H (n ϭ 2), A455E (n ϭ 2), R1066H (n ϭ 1), S13F (n ϭ 1), and 1898ϩ3AϾG (n ϭ 1). Login to comment
178 Two patients carried A455E/F508 and 2 carried A455E/621ϩ1GϾT. Munck27 reported acute pancreatitis as a presenting symptom during heat stroke for 3 patients with CF; 1 patient had PS and a fecal elastase level of 500 ␮g/g feces, and the others had moderate PI and stool elastase levels of 102 and 162 ␮g/g. Login to comment
188 A455E, the Dutch mutation, is considered a class IV mutation but 50% to 75% of patients were reported to have PI.26 G85E, the Mediterranean mutation, was reported by Durno et al13 with PS, but it is actually a class II mutation with some variability in pancreatic function.28 In the present study, well-accepted methods of stool analysis (fat loss of Ͼ7 g/day or elastase levels of Ͻ200 ␮g/g stool) were chosen to determine pancreatic status as PS or PI. Login to comment

PMID: 15775760 [PubMed] Ruchon AF et al: "Frequency and phenotypic consequences of the 3199del6 CFTR mutation in French Canadians."

No. Sentence Comment

67 A pancreatic sufficiency phenotype was found in two patients carrying A455E on the second allele, consistent with the previously reported association of A455E with a mild CF phenotype.6 In two patients, a second CF-causing mutation was not identified despite the use of a 35 mutation panel, which included the 25 ACMG recommended mutations. Login to comment
88 Phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment

PMID: 15784035 [PubMed] Gallegos-Orozco JF et al: "Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis."

No. Sentence Comment

55 CFTR Mutations and Associated Phenotype Classic Nonclassic Cystic Fibrosis Cystic Fibrosis Variant Normal 621 + 1G→T R117H G85E* 7T 711 + 1G→T R334W 5T† 9T 1078delT R347P M470V‡ F508C I507 A455E I507V F508 2789 + 5G → A I506V 1717 - 1G→A 3849 + 10kbC→T G542X G551D R553X R560T R1162X 3659delC W1282X N1303K * Classic cystic fibrosis and nonclassic cystic fibrosis. Login to comment

PMID: 15789152 [PubMed] Langfelder-Schwind E et al: "Cystic fibrosis prenatal screening in genetic counseling practice: recommendations of the National Society of Genetic Counselors."

No. Sentence Comment

156 Mutations described as "mild", for example, R117H, R334W, R347P, and A455E (Kristidis et al., 1992; The CF genotype-phenotype consortium, 1993), are more likely to be associated with pancreatic sufficiency regardless of the class of the second mutation. Login to comment

PMID: 15868140 [PubMed] Moskowitz SM et al: "Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment."

No. Sentence Comment

71 Modifier genes as modulators of CF lung phenotype Some DF508 homozygous individuals develop severe obstructive lung disease during the first and second decades of life despite maximal medical therapy, while others with the same genotype have little or no obstructive lung disease despite minimal therapy during Table 2 Examples of disease-associated CFTR alleles CFTR allele Allele class Usual clinical status (when compounded with a severe CFTR allelea ) Allele frequency in Caucasiansb General populationc CF CAVD G542X (9T) 1 Pancreatic-insufficient CF 0.001 0.023 0.003 DF508 (9T) 2 Pancreatic-insufficient CF 0.012-0.016 0.694 0.20 G551D (7T) 3 Pancreatic-insufficient CF 0.001 0.022 0.01 R117H (5T) 4 Pancreatic-sufficient CF 0.0001 0.004 ND R117H (7T) 4 CAVD or carrier 0.002-0.003 0.003 0.04 A455E (9T) 5 Pancreatic-sufficient CF ND 0.001 ND 3849+10kbC fi T 5 Pancreatic-sufficient CF ND 0.007 ND WT (5T) 5 CAVD or carrier 0.042 d 0.19 Other allelese 1-5 Variable 0.002-0.006 0.247 0.55 WT (7T or 9T) Wild-type Carrier 0.935 e e a Severe CFTR allele is defined as a class 1, 2, or 3 allele. Login to comment

PMID: 15870824 [PubMed] Stuppia L et al: "Screening of mutations in the CFTR gene in 1195 couples entering assisted reproduction technique programs."

No. Sentence Comment

64 of detected carriers Prevalence among detected CFTR mutations DF508 40 (3.34%) 65.58% DI507 0 0 G542X 6 (0.50%) 9.84% 1717-1G-A 1 (0.08%) 1.64% G551D 0 0 R553X 0 0 R560T 0 0 Q552X 0 0 W1282X 7 (0.58 %) 11.48% S1251N 0 0 N1303K 3 (0.20%) 4.91% 394delTT 0 0 G85E 3 (0.25%) 4.91% E60X 0 0 621+1G-T 0 0 R117H 0 0 1078delT 0 0 R347P 0 0 R334W 0 0 2143delT 0 0 2183AA-G 0 0 2184delA 0 0 711+5G-A 0 0 2789+5G-A 1 (0.08%) 1.64% R1162X 0 0 3659del5 0 0 3849+10kbC-T 0 0 A455E 0 0 5T 78 (6.52%) Table 2 Distribution of CFTR mutations and 5T allele according to phenotype for the 1195 individuals Phenotype CF/WT 5T/WT CF/5T WT/WT Infertile males (non-CBAVD), N ¼ 304 20 (6.58%) 30 (9.87%) 0 254 (83.55%) Infertile males (CBAVD), N ¼ 16 0 10 (62.50%) 6 (37.50 %) 0 Infertile females, N ¼ 93 5 (5.37%) 7 (7.53%) 0 81 (87.10%) Unexplained infertility, N ¼ 782 30 (3.84%) 31 (3.96%) 0 721 (92.20%) Total ¼ 1195 55 (4.60%) 78 (5.50%) 6 (0.50%) 1056 (88.40%) CFTR alteration was detected, including a mutation in three cases and the 5T polymorphism in the remaining six. Login to comment

PMID: 15888700 [PubMed] Rowe SM et al: "Cystic fibrosis."

No. Sentence Comment

124 The A455E mutation (class IV) exhibits onlypartialCFTRion-channelactivity,afeaturethat probably explains a less severe pulmonary phenotype.47 Other mutation classes include reduced numbers of CFTR transcripts (class V) and defective CFTR stability at the cell surface (class VI).48-50 Insight into the cellular consequences of defective CFTR suggests a role for tailored therapies, a predominant theme in clinical research on cystic fibrosis. Login to comment

PMID: 15908456 [PubMed] Sanchez-Garcia JF et al: "Multiple mutation analysis of the cystic fibrosis gene in single cells."

No. Sentence Comment

62 G, R1162X, 3659delC, W1282X, 3905insT, N1303K, 1078delT, R347P, R347H and R334W labelled with TET (green) and A455E, 1898þ1G.A, 2183AA.G, 2789þ5G.A, G85E, 621þ1G.T, R117H, Y122X and 711þ1G.T labelled with HEX (yellow). Login to comment

PMID: 15948195 [PubMed] Quint A et al: "Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening."

No. Sentence Comment

37 In this group we revealed two additional mutations L165S and A455E, each was identified on a single chromosome and one mutation remained unidentified. The relative frequencies of the Ashkenazi founder mutations in Ashkenazi patients were W1282X (43%), DF508 (33%), G542X (10%), 3849 þ 10 kb C!T (5%), N1303K (5%), and 1717 (1%). Login to comment
58 Mutations in the CF Bearing Alleles in the Jewish Patients According to the Ethnic Origin Country of origin Ashkenazi Morocco Tunisia Balkan Iraq Iran/ Kurdistan Georgia Yemen Total Number of alleles (%) 193 (69.0) 34 (12.1) 12 (4.3) 21 (7.5) 8 (2.8) 3 (0.7) 8 (2.8) 2 (0.7) 281 W1282X (%) 83 (42.8) 1 (8.3) 4 (19.0) 88 (31.3) DF508 (%) 65 (33.5) 24 (70.6) 3 (25.0) 7 (33.3) 1 100 (35.6) N1303K (%) 10 (5.2) 10 (3.6) G542X (%) 19 (10.3) 4 (19.0) 24 (8.5) 3849-10 kbC!T (%) 10 (5.1) 1 (2.9) 2 (9.5) 13 (4.6) 1717-1G!A (%) 2 (1.0) 2 (0.7) D1152H (%) 1 (0.5) 1 (0.4) S549R (T!G) (%) 4 (11.8) 4 (1.4) G85E (%) 2 (9.5) 2 (0.7) 405 þ 1G!A (%) 8 (66.7) 8 (2.8) Y1092X (%) 3 (37.5) 3 (1.1) W1089X (%) 2 (9.5) 2 (0.7) Q359K/T360K (%) 8 (100) 8 (2.8) I1234V (%) 2 (100) 2 (0.7) 2751 þ 1insT (%) 2 (25.0) 2 (0.7) 3121-1G > A (%) 1 1 (0.4) M952I (%) 1 (12.5) 1 (0.4) L165S (%) 1 (0.5) 1 (0.4) A455E (%) 1 (0.5) 1 (0.4) L997F (%) 1 (2.9) 1 (0.4) G1244E (%) 1 (2.9) 1 (0.4) Unkown (%) 1 (0.5) 3 (8.8) 2 (25.0) 1 7 (2.5) Mutation Spectrum in Jewish CF Patients [Wahab, 2003]. Login to comment

PMID: 15994263 [PubMed] de Gracia J et al: "Genotype-phenotype correlation for pulmonary function in cystic fibrosis."

No. Sentence Comment

185 Although there are a few rare mutations such as A455E and R117H which are clearly linked to a better pulmonary outcome,12 13 the effect on the lungs of F508del and most other mutations cannot be separated and attempts to link mutations in CFTR to severity of lung disease have been unsuccessful.14 Furthermore, genes other than CFTR and environmental factors such as access to specialised centres and treatment strategies may be more important factors in modifying the development, progression, and severity of pulmonary disease. Login to comment
251 The mild pulmonary phenotype seen in patients with genotype I-II/III-V is consistent with previous reports where a few rare mutations such as A455E, R117H, 3849+10kbCRT, 2789+5GRT, and P67L (all class IV or V mutations) are clearly linked to a better pulmonary outcome.13 14 26-28 The findings observed in this study support the hypothesis that differences in CF pulmonary phenotype could be related to the effect of the genotype on CFTR protein production and function. Nevertheless, it is important to recognise that specific mutations may have characteristics of more than one 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 20 30 40 50 60 Follow up (years) Events Lung transplant Dead I-II/I-II 9 6 I-II/III-V 1 0 Genotype I-II/III, IV or V I-II/I-II p<0.001 (Log-rank test for trend) Figure 3 Kaplan-Meier survival curves by genotype. Login to comment

PMID: 16088579 [PubMed] Gallati S et al: "Genetics of cystic fibrosis."

No. Sentence Comment

43 Mutations (missense, nonsense, frameshift, splice, small and large in-frame deletions or insertions) con- Table 1 Distribution of theWorldwide 24 Most Common Cystic Fibrosis Mutationsa Exon/ Northern Southern North South Austral- Relative Mutation Intron Europe Europe America America asia Africa Asia Frequency G85E E 03 30 14 16 n.a. n.a. 0 7 0.15 R117H E 04 62 3 61 n.a. 7 0 0 0.30 621+1G→T I 04 97 37 154 n.a. 27 0 0 0.72 711+1G→T I 05 15 13 21 n.a. n.a. n.a. 0 0.11 1078delT E 07 53 2 1 n.a. 1 n.a. 0 0.13 R334W E 07 18 21 12 n.a. 2 0 0 0.12 R347P E 07 55 24 26 n.a. 1 0 0 0.24 A455E E 09 35 0 27 n.a. n.a. n.a. 0 0.14 ⌬I507 E 10 57 5 20 2 9 0 0 0.21 ⌬F508 E 10 14,866 4007 6901 342 2309 351 173 66.02 1717-1G→A I 10 160 65 44 n.a. 12 0 3 0.65 G542X E 11 439 259 234 38 56 9 27 2.42 S549N E 11 18 2 5 1 3 1 0 0.07 G551D E 11 356 37 206 1 117 0 0 1.64 R553X E 11 165 44 96 5 11 1 0 0.73 R560T E 11 40 0 24 0 3 0 0 0.15 1898+1G→A I 12 41 10 2 n.a. n.a. n.a. 0 0.12 2184delA E 13 14 7 8 n.a. n.a. n.a. 0 0.07 2789+5G→A I 14b 27 10 17 n.a. n.a. n.a. 0 0.12 R1162X E 19 36 68 19 0 2 0 0 0.28 3659delC E 19 39 1 14 n.a. n.a. n.a. 0 0.12 3849+10kbC→T I 19 23 8 57 n.a. n.a. n.a. 16 0.24 W1282X E 20 120 43 245 n.a. 6 2 120 1.22 N1303K E 21 209 179 130 11 23 8 29 1.34 Chromosomes 21,154 7281 10438 758 3095 515 608 screened Detection rate 80.2 66.7 79.9 52.8 83.7 72.2 61.7 aAccording to the Cystic Fibrosis Genetic Analysis Consortium, http://www.genet.sickkids.on.ca/cftr/. Login to comment
59 ClassV: Reduced Synthesis and/orTrafficking Various mutations are associated with reduced biosynthesis of fully active CFTR due to partially aberrant splicing (3849+10kbC→T, T5),21,22 promotor mutations or inefficient trafficking (A455E).23 These mutations result in reduced amounts of functional gene products and thus in milder CF phenotypes. Login to comment
67 SSCP analysis is one of the most popular methods for the detection of sequence variants in polymerase chain reaction (PCR) amplified DNA fragments.29 The princi- Table 3 Cystic Fibrosis Mutations Detected by Commercial Kits INNO-LiPA Mutations CF2 ⌬F508, ⌬I507, G542X, 1717-1G→A, G551D, R553X, W1282X, N1303K CFTR12 ⌬F508, ⌬I507, G542X, 1717-1G→A, G551D, R553X, W1282X, N1303K, S1251N, R560T, 3905insT, Q552X CFTR17+Tn 394delTT, G85E, 621+1G→T, R117H, 1078delT, R347P, R334W, E60X, 2183AA→G, 2184delA, 711+5G→A, 2789+5G→A, R1162X, 3659delC, 3849+10kbC→T, 2143delT, A455E, (5T/7T/9T) Elucigene CF4 ⌬F508, G542X, G551D, 621+1G→T CF12 ⌬F508, G542X, G551D, N1303K, W1282X, 1717-1G→A, R553X, 621+1G→T, R117H, R1162X, 3849+10kbC→T, R334W CF20 1717-1G→A, G542X, W1282X, N1303K, ⌬F508, 3849+10kbC→T, 621+1G→T, R553X, G551D, R117H, R1162X, R334W, A455E, 2183AA→G, 3659delC, 1078delT, ⌬I507, R345P, S1251N, E60X CF Poly-T 5T/7T/9T OLA CF OLA assay ⌬F508, F508C, ⌬I507, Q493X, V520F, 1717-1G→A, G542X, G551D, R553X, R560T, S549R, S549N, 3849+10kbC→T, 3849+4A→G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621+1G→T, R117H, Y122X, 711+1G→T, 1078delT, R347P, R347H, R334W, A455E, 1898+1G→A, 2183AA→G, 2789+5G→A b Figure 2 Mutation screening of exon 19 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene using polymerase chain reaction (PCR) followed by single-strand conformation polymorphism/heteroduplex (SSCP/HD) analysis on a silver-stained polyacrylamide gel. Login to comment

PMID: 16101453 [PubMed] Suh KS et al: "Intracellular chloride channels: critical mediators of cell viability and potential targets for cancer therapy."

No. Sentence Comment

86 A variety of other mutations have been detected in CF patients [39] leading to ablation of protein synthesis (nonsense G542X, frameshift 394delTT, or splice junction 1717 G/A), blocked protein processing (missense N1303K or AA deletion in F508), blocked protein regulation (missense at G551D), altered conductance (missense R117H or R347P), and reduced protein synthesis (missense A455E, alternative splicing 3849 + 10kbC/T) [40]. Login to comment

PMID: 16124861 [PubMed] Cutting GR et al: "Modifier genetics: cystic fibrosis."

No. Sentence Comment

42 Patients carrying a substitution of glutamic acid for alanine at codon 455 (A455E) have a slower rate of decline in lung function (30, 49). Login to comment

PMID: 16132229 [PubMed] Eudes R et al: "Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations."

No. Sentence Comment

132 Worth noting is that A455E and P574H are mild alleles, as they have been found associated with preserved pancreatic function and residual secretion of chloride; in addition, a correlation between the A455E mutation and mild pulmonary disease has also been reported [38]. Login to comment
336 333: 95-99 39 De Braekeleer M., Allard C., Leblanc J. P., Simard F. and Aubin G. (1997) Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Hum. Genet. 101: 208-211 40 Van Oene M., Lukacs G. L. and Rommens J. M. (2000) Cystic fibrosis mutations lead to carboxyl-terminal fragments that highlight an early biogenesis step of the cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 275: 19577-19584 41 Ostedgaard L. S., Zeiher B. and Welsh M. J. (1999) Processing of CFTR bearing the P574H mutation differs from wild-type and deltaF508-CFTR. Login to comment

PMID: 16179637 [PubMed] Plant BJ et al: "Cystic fibrosis, disease severity, and a macrophage migration inhibitory factor polymorphism."

No. Sentence Comment

114 Recent work has suggested that the A455E (30, 34), 3849ϩ10 kb C→T (30, 35), and 2789ϩ5G→A (30, 36) are associated with mild clinical manifestations; these CFTR mutations were not seen in our patient population. Login to comment

PMID: 16191501 [PubMed] Chou LS et al: "A comparison of high-resolution melting analysis with denaturing high-performance liquid chromatography for mutation scanning: cystic fibrosis transmembrane conductance regulator gene as a model."

No. Sentence Comment

18 Materials and Methods Sample Source and Study Design Eleven commercially genotyped samples were obtained from Coriell Cell Repositories, Coriell Institute for Medical Research, Camden, NJ (Y122X, R334W, R347P, A455E, I507del, F508del, F508C, G542X/G542X, R553X, R560T, and M1101K). Login to comment
31 ❚Table 1❚ Mutations Analyzed in the Study Position From 5' Exon (or Intron) Genotype* No. of Samples Nucleotide Change SNP Class† End/Amplicon Size (bp) 3 394delTT 1 Del‡ - 132/234 4 R117H 1 G→A 1 83/270 Y122X 1 T→A 4 99/270 I148T 2 T→C 1 176/270 Intron 4 621+1 2 G→T 2 233/270 7 R334W 1 C→T 1 208/345 R347P 1 G→C 3 248/345 9 A455E 2 C→A 2 155/263 10 I507del 1 Del‡ - 171/292 F508del 3 Del‡ - 174/292 F508del/F508del 1 Del - 174/292 F508C 1 T→G 2 175/292 11 G542X 1 G→T 2 90/175 G542X/G542X 1 G→T 2 90/175 G551D 1 G→A 1 118/175 R553X 2 C→T 1 123/175 R560T 1 G→C 3 145/175 13 2184delA 1 Del‡ - 356/458 17b M1101K 1 T→A 4 196/292 21 N1303K 1 C→G 3 175/250 bp, base pairs; SNP, single nucleotide polymorphism. Login to comment
75 Additional mutations in exons 9, 10, 11, and 21 included 7 heterozygous SNPs (A455E, F508C, G542X, G551D, R553X, R560T, and N1303K) and 2 heterozygous 3-base deletions (I507del and F508del). Login to comment

PMID: 16202788 [PubMed] Rock MJ et al: "Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing."

No. Sentence Comment

30 Mutations included in this assay are 2184delA, A455E, DI507, DF508, G542X, G551D, R553X, R560T, 1717-1G>A, R1162X, 3659delC, N1303K, W1282X, R334W, R347P, 1078delT, R117H, I148T, 62111G>T, 278915G>A, 3849110kbC>T, G85E, 109811G>A, 71111G>T and 312011G>A. Login to comment

PMID: 16202790 [PubMed] Sontag MK et al: "Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes."

No. Sentence Comment

86 The pancreatic sufficient mutations identified were 18981 5G>T, 278915G>A, A455E, G551S, G85E, I336K, P67L, R117C, R117H, R334W, R347P. Login to comment
129 Initial and repeat sweat chloride values and CFTR mutations in infants with borderline sweat test results Sweat Cl2 (mmol/L) Infant <6 months >6 months Genotype A 55 65 DF508/A455E B 50 - DF508/R117H C 45 77 DF508/R117C (7T/9T) D 33 26 DF508/- E 43 76 R117H/F575Y (7T,7T) F 43 25 312011G-A/- Figure 4. Login to comment

PMID: 16227367 [PubMed] McWilliams R et al: "Cystic fibrosis transmembrane regulator gene carrier status is a risk factor for young onset pancreatic adenocarcinoma."

No. Sentence Comment

277 R McWilliams Department of Oncology and Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA W E Highsmith Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA K G Rabe, M de Andrade, L A Tordsen Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA Conflict of interest: None declared. Table 1 Comparison of CFTR mutation frequencies detected in the young onset pancreatic cancer cohort versus the clinical database Young onset pancreatic cancer cases (,60 y old at diagnosis, n = 166) Mayo Clinic clinical database reference group (n = 5349) No % No % CFTR mutation non-carriers 152 91.6 5132 95.9 CFTR mutation carriers 14 8.4 217 4.1 Mutation distribution DF508 12 85.7 155 71.4 R177H 1 7.1 28 12.9 G551D 6 2.8 2789+5G.A 6 2.8 G542X 4 1.8 N1303K 1 7.1 3 1.4 1717-1G.T 2 0.9 3849+10kbC.T 2 0.9 A455E 2 0.9 R1162X 2 0.9 R347H 1 0.5 R553X 1 0.5 3905insT 1 0.5 621+1G.T 1 0.5 W1282X 1 0.5 1898+1G.A 1 0.5 R560T 1 0.5 Young onset pancreatic cancer cases were more frequent carriers of the CFTR mutations compared with patients in the control database (odds ratio 2.18 (95% confidence interval 1.24-3.29); p = 0.006). Login to comment

PMID: 16243854 [PubMed] Massie J et al: "Markedly elevated neonatal immunoreactive trypsinogen levels in the absence of cystic fibrosis gene mutations is not an indication for further testing."

No. Sentence Comment

222 *All patients underwent an extended CFTR mutation analysis for the following mutations in addition to DF508: G551D, R553X, G542X, R117H, N1303K, 621+1G-T, A455E, V520F, 1717-1G-A, W1282X, R1162X, 3849+10kbC-T, R347P, R334W, R560T, S549N. Login to comment

PMID: 16258369 [PubMed] Gullo L et al: "Mutations of the CFTR gene in idiopathic pancreatic hyperenzymemia."

No. Sentence Comment

52 A (i) 5 1078delT, R347P, R334W 7 A455E, Tn (i) 8, 9 DF508, DI507 10 G542X, 1717-1 G . Login to comment

PMID: 16429424 [PubMed] Choi EH et al: "Association of common haplotypes of surfactant protein A1 and A2 (SFTPA1 and SFTPA2) genes with severity of lung disease in cystic fibrosis."

No. Sentence Comment

16 So far, there has been no evidence to correlate common mutations in CFTR, particularly DF508, with pulmonary deterioration, the most common complication of CF.1,2 There are rare mutations, such as A455E, that appear to correlate with milder pulmonary disease.3 There is, however, a strong correlation between selective CFTR mutations and pancreatic disease.4,5 A wide variation in pulmonary disease within families harboring identical CFTR mutations has led many experts to postulate that environmental and secondary genetic factors, also known as modifying genes (CF modifiers), could be important.6,7 It was demonstrated in animal models that genetic modifiers can influence outcomes in CF: there was an observed difference in severity of both intestinal and lung disease between CF micewith different genetic backgrounds.8,9 A genetic linkage analysis suggested that a modifier gene for meconium ileus is located in the proximal region of mouse chromosome 7, which is syntenic with human chromosome 19q13.9,10 1 Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Login to comment
74 None of the rare CFTR mutations previously associated with mild pulmonary disease, such as A455E, was included.3 There was no significant association between primary CFTR mutations and the following measured pulmonary parameters: FEV1, scores for ATS, AMA, dyspnea, physical grade, Shwachman-and Kulczycki, and PA colonization. Login to comment

PMID: 16435054 [PubMed] Zilfalil BA et al: "Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays."

No. Sentence Comment

55 MUTATIONS R553X G551D 1507 del F508 del 1717-1 G>A G542X R560T R347P W1282X R334W 1078 Del T 3849 + 10KB C>T R1162X N1303K 3659 Del C A455E R117H 2183 AA>G 2789+5 G>A 1898 +1 G>A 621+1 G>T 711+1 G>T G85E S549N S549R V520F Q493X R347H 3849 +4 A>G 3905 INS T Y122X 4 software before running the gel electrophoresis in 1X TBE using ABI PRISM® 377 Genetic Analyzer (Applied Biosystems, USA) for 45 minutes. Login to comment

PMID: 16443646 [PubMed] Van Goor F et al: "Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules."

No. Sentence Comment

387 Genotype/phenotype correlations of Cl-channel function with disease severity show that mutations resulting in a only modest recovery toward wild-type levels (e.g., 5-30%) increase in CFTR expression or activity (e.g., A455E, 2,789 ϩ 5G3A, 5T, R334W, R347P, and R117H) and are typically associated with pancreatic sufficiency, a slower rate of pulmonary function decline, and a better severity index than that shown in patients with severe disease genotypes (5, 6, 10, 36, 49). Login to comment

PMID: 16472140 [PubMed] Becq F et al: "On the discovery and development of CFTR chloride channel activators."

No. Sentence Comment

52 Class V mutations (e.g. A455E, P574H) produce functional proteins with normal Cl-channel activity and regulation but at reduced rate of synthesis [19]. Login to comment

PMID: 16648884 [PubMed] Mishra A et al: "The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era."

No. Sentence Comment

117 In addition, at least for R117H, the amount of time that the channel is open is also reduced.75 R117H is a particularly interesting mutation as the affected CFTR function is also determined by the M470V polymorphism and the amount of protein produced.69,76 The clinical effects vary from pancreatic insufficient CF through to no clinical disease depending on the combination of these factors.77 Class V: Reduced Abundance Mutations in this group include missense, e.g. A455E (substitution of glutamic acid for alanine) and aberrant exon splicing, e.g. 3849 10kbC→T and the intron 8 polythymidine and TG repeat sequences that regulate exon 9 splicing.67,78 These mutations produce a reduced amount of CFTR transcript and low levels of functional protein that is translocated to the cell membrane. Login to comment
244 Highsmith and colleagues (1994) studied 23 patients with pulmonary disease characteristic of CF but with a normal sweat test and identified a point mutation in intron 19 of the CFTR gene, termed 3849+10kb C-T.15 This mutation produces an alternative splicing site and decreased amounts of CFTR mRNA can be detected.16 Thus, according to the classification of the CFTR mutations, this mutation falls into Class V.16,67 Other mutations associated with normal or borderline sweat electrolytes are R117H, D1152H, A455E, G551S and 2789+5G - A.9,24,78 An interesting phenotype, presenting with elevated sweat chloride concentration in the absence of other CF symptoms, has been described in a patient with a nonsense mutation, S1455X.105 This mutation truncates 26 amino acids from the C-terminus of the protein product. Login to comment

PMID: 16690975 [PubMed] McKone EF et al: "Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease."

No. Sentence Comment

63 Mild CFTR mutations (Class IV and V) ϭ R117H, R334W, G85E, R347P, 3849ϩ10KbC→T, 2789ϩ5G→A, A455E. Login to comment

PMID: 17003641 [PubMed] Keiles S et al: "Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis."

No. Sentence Comment

71 Patients With 1 CFTR Mutation CFTR Mutation 1 No. of Patients 1717-1 G9A 1 2789+5 G9A 1 3849+10kb C9T 2 3849+45 G9A 1 621+3 A9G 2 A1364V 1 A349V 1 A455E 1 D1152H 1 D1445N 1 deltaF508 16 E217G 1 F1286C 1 F316L 1 G542X 1 G551D 1 I148T 1 I807M 1 L206W 1 L967S 2 L997F 2 P55S 1 Q179K 1 Q220X 1 R117H 3 R1453W 1 R297Q 1 R31C 1 R668C 2 S1235R 1 S573C 1 S945L 1 V562A 1 V754M 2 Y1092X 1 Total patients 58 MutationsinboldfacewouldnothavebeendetectedbytheACOG/ACMGmutationpanel. Login to comment

PMID: 17099022 [PubMed] McKone EF et al: "CFTR genotype as a predictor of prognosis in cystic fibrosis."

No. Sentence Comment

46 Alleles High-risk CFTR genotype Class I 2,131 G542X, R553X, W1282X, R1162X, 621-1G3T, 1717-1G3A, 1078⌬T, 3659⌬C Class II 11,231 ⌬F508, ⌬I507, N1303K, S549N, G85E Class III 783 G551D, R560T Low-risk CFTR genotype Class IV 391 R117H, R334W, R347P Class V 421 3849 ϩ 10KbC3T, 2789 ϩ 5G3A, A455E *Patients with both CFTR alleles in either class I, class II, or class III were grouped together as a high-risk genotype, while patients with at least one mutant allele in class IV and V were considered to have low-risk genotypes; 380 patients had both mutations in either class I, II, or III, while 314 patients had both mutations in either class IV or V (total, n ϭ 15,651). Login to comment

PMID: 17375191 [PubMed] Daksis JI et al: "Heteropolymeric triplex-based genomic assay to detect pathogens or single-nucleotide polymorphisms in human genomic samples."

No. Sentence Comment

125 Sequence bglIR-WT25C 1 59-TATTTTGATTATAGGACATGAAGAT-39 DR01-WT15 2 59-GAGCCGAAGGGGCAG-39 CFTR delta F508-WT25C 3 59-TAGGAAACACCAAAGATGATATTTT-39 CFTR delta F508-MUT25C 4 59-ATAGGAAACACCA---ATGATATTTTCT-39 CFTR delta I507-WT25C 5 59-TAGGAAACACCAAAGATGATATTTT-39 CFTR delta I507-MUT25C 6 59-ATAGGAAACACCAAAGA---TATTTTCT-39 CFTR 3659delC-WT25C 7 59-TGGTTTGGTTGACTTGGTAGGTTTA-39 CFTR 3659delC-MUT25C 8 59-ATGGTTTGGTTGACTTG-TAGGTTTA-39 CFTR 3849+10kbCRT-WT25C 9 59-GTGTCTTACTCGCCATTTTAATACT-39 CFTR 3849+10kbCRT-MUT25C 10 59-GTGTCTTACTCACCATTTTAATACT-39 CFTR 2789+5GRA-WT25C11 59-AATAGGACATGGAATACTCACTTTC-39 CFTR 2789+5GRA-MUT25C 12 59-AATAGGACATGGAATATTCACTTTC-39 CFTR G551D-WT25C 13 59-ATTCTTGCTCGTTGACCTCCACTCA-39 CFTR G551D-MUT25C 14 59-ATTCTTGCTCGTTGATCTCCACTCA-39 CFTR 621+1GRT-WT25C 15 59-AAGTATTACCTTCTTATAAATCAAA-39 CFTR 621+1GRT-MUT25C16 59-AAGTATTAACTTCTTATAAATCAAA-39 CFTR R1162X-WT25C 17 59-AACTTAAAGACTCGGCTCACAGATC-39 CFTR R1162X-MUT25C 18 59-AACTTAAAGACTCAGCTCACAGATC-39 CFTR 1717-1GRA-WT25C 19 59-TGGAGATGTCCTATTACCAAAAATA-39 CFTR 1717-1GRA- MUT25C 20 59-TGGAGATGTCTTATTACCAAAAATA-39 CFTR A455E-WT25C 21 59-CCAGCAACCGCCAACAACTGTCCTC-39 CFTR A455E-MUT25C 22 59-CCAGCAACCTCCAACAACTGTCCTC-39 CFTR G542X-WT25C 23 59-ATTCCACCTTCTCCAAGAACTATAT-39 CFTR G542X-MUT25C 24 59-ATTCCACCTTCTCAAAGAACTATAT-39 CFTR N1303K-WT25C 25 59-TAGGGATCCAAGTTTTTTCTAAATG-39 CFTR N1303K-MUT25C 26 59-TAGGGATCCAACTTTTTTCTAAATG-39 CFTR R560T-WT25C 27 59-AGTTATTCACCTTGCTAAAGAAATT-39 CFTR R560T-MUT25C 28 59-AGTTATTCACGTTGCTAAAGAAATT-39 CFTR W1282X-WT25C 29 59-TTTCCTCCACTGTTGCAAAGTTATT-39 CFTR W1282X-MUT25C 30 59-TTTCCTTCACTGTTGCAAAGTTATT-39 MTHFR C677T-WT25C 31 59-TGATGATGAAATCGGCTCCCGCAGA-39 MTHFR C677T-MUT25C 32 59-TGATGATGAAATCGACTCCCGCAGA-39 FVL G1691A-WT25C 33 59-CCCTCTGTATTCCTCGCCTGTCCAG-39 FVL G1691A-MUT25C 34 59-CCCTCTGTATTCCTTGCCTGTCCAG-39 All 25-mer probes listed were antisense. Login to comment
704 Mutation Source Number of tests Percentage GC in probe sequence Percentage difference of mismatched TAF relative to perfect match TAF CFTR delta F508 blood 102 28% 2100% to 281% CFTR delta I507 blood 6 28% 2100% to 285% CFTR 3659delC blood 11 40% 2100% to 255% CFTR 3849+10kbCRT blood 9 36% 2100% to 282% CFTR 2789+5GRA blood 16 36% 2100% to 275% CFTR 2789+5GRA saliva 13 36% 2100% to 266% CFTR G551D blood 11 48% 2100% to 261% CFTR 621+1GRT blood 5 20% 2100% to 257% CFTR R1162X blood 6 44% 267% to 236% CFTR 1717-1GRA blood 12 32% 2100% to 258% CFTR A455E blood 9 60% 2100% to 289% CFTR G542X blood 6 36% 2100% to 260% CFTR N1303K blood 8 32% 2100% to 283% CFTR R560T blood 6 28% 2100% to 254% CFTR W1282X blood 14 36% 2100% to 274% MTHFR C677T blood 55 52% 2100% to 272% FVL G1691A blood 34 60% 2100% to 281% TAF indicates Triplex-Associated Fluorescence. doi:10.1371/journal.pone.0000305.t004 ..................................................................................... brighter when intercalated into complexes of identical short oligonucleotides, such as the probes used in our assay, than when a like number of YOYO-1 molecules were in the presence of genomic duplex DNA. Login to comment

PMID: 17471160 [PubMed] Huang CK et al: "Validation of cystic fibrosis mutation analysis using ABI 3130XL genetic analyzer."

No. Sentence Comment

58 Mutation controls: to specifically assess the detection of CF mutations, 20 cell line DNA samples with mutations of R553X, 3659delC/delF508, delF508/Q493X, 711+ 1G>T/621+1G>T, 621+1G>T/delF508, G85E/ 621+1G>T, R560T/delF508, A455E/621+1G>T, N1303K, W1282X, G551D/R553X, 2789+5G>A/ 2789+5G>A, 3849+10C>T/3849+10C>T, 1717-1G>A, delF508/delF508, R347P/G551D, R334W, V520F, R117H/delF508/5T/9T, or G542X/G542X, respectively, from the Coriell Cell Repositories were analyzed. Login to comment

PMID: 17627383 [PubMed] Knezevic J et al: "Analysis of cystic fibrosis gene mutations and associated haplotypes in the Croatian population."

No. Sentence Comment

39 INNOGENETICS INNO-LIPA CFTR 12 and INNO-LIPA CFTR 7 ϩ Tn diagnostic kits were used to assess the presence of the 29 mutations in CF patients; ⌬F508, ⌬I507, G542X, N1303K, 1717-1G Ǟ A, W1282X, G551D, R553X, S1251N, R560T, 3905insT, Q552X, 394delTT, G85E, E60X, 621 ϩ 1G Ǟ T, R117H, 1078delT, R347P, R334W, 2143delT, 2183AA Ǟ G, 2184delA, 711 ϩ 5G Ǟ A, 2789 ϩ 5G Ǟ A, R1162X, 3659delC, 3849 ϩ 10kbC Ǟ T, and A455E. Login to comment

PMID: 17850636 [PubMed] Girardet A et al: "Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements."

No. Sentence Comment

34 If IRT at day 3 is positive (.65 ng/ml), the card is subjected to an ARMS Elucigen kit (Tepnel) testing for 30 common CF mutations (F508del, Y1092X, 1717-1G.A, G542X, W1282X, N1303K, 3849110kbC.T, 394delTT, 62111G.T, S1251N, G551D, R117H, R1162X, R334W, A455E, 2183AA.G, 3659delC, 1078delT, I507del, R347P, R553X, E60X, 1 8 1 1 11 . Login to comment

PMID: 17890437 [PubMed] Montgomery J et al: "Scanning the cystic fibrosis transmembrane conductance regulator gene using high-resolution DNA melting analysis."

No. Sentence Comment

145 2 223CϾT R31C 3 355CϾT R75X 386GϾA G85E 4 482GϾA R117H 575TϾC I148T 621 ؉ 1GϾTb 5 711 ؉ 1GϾT 7 1078delT 1132CϾT R334W 1150delA 1172GϾC R347P 8 1341 ϩ 18AϾCc 9 1496CϾA A455E 10 1651-1653del I507del 1653-1655del F508deld 11 1717 - 1GϾA 1756GϾT G542Xe 1784GϾA G551Db 1789CϾT R553Xf 1811GϾC R560T 12 1898 ؉ 1GϾA 13 2184delA 14b 2789 ؉ 5GϾAe 16 3120 ؉ 1GϾA 18 3500 - 2AϾTg 19 3616CϾT R1162X 3659delC Intron 19 3849 ؉ 10kbCϾTe 20 3978GϾA W1282X 21 4041CϾG N1303K 22 4178GϾA G1349Dc a Disease-causing variants recommended for genotyping by the ACMG (4) are in bold. Login to comment

PMID: 17949287 [PubMed] Lebo RV et al: "One multiplex control for 29 cystic fibrosis mutations."

No. Sentence Comment

118 Replacing modified sequences near the A455E and N1303K mutations in clone #9 The initial clone 9 insert consisted of three amplicon fragments: (Fig. 2, #9, left) the 5Ј CFTR genomic segment with A455E from exon 9 and 5T from intron 8; (Fig. 2, #9, center) a middle segment with the 3849ϩ10kbC Ǟ T mutation in intron 19; and (Fig. 2, #9, right) the 3Ј insert with the N1303K mutation from exon 21 that all tested appropriately on the Innogenetics test strips (Fig. 3, f 9 strip pair). Login to comment
120 However, 10 nucleotide substitutions were found 34 to 257 basepairs downstream of the A455E site. Login to comment
133 Instead, our laboratory has prepared multiplex controls from aliquots of lin- MULTIPLEX CYSTIC FIBROSIS CONTROL 261 1 2 3 4 5 6 7 8 9 EXON/INTRON 4F4 R4 F11 R11INTRON 10/EXON 11 EXON 7R7 F7 R5 F9INTRON 5 R347P R334W 1078delT EXON 10R10 F10 R11 F11EXON 11/INTRON 10 INTRON 16R16 F16 R14b F14bINTRON 14b EXON 19F19 R19 F20 R20EXON 20 R1162X 3659delC INTRON 8/EXON 9F9 R9 F119 R119INTRON 19 5T A455E F21 R21EXON 21 N1303K EXON 10F10 R10 F3 R3EXON 3 1507 INTRON 12F12 R12 EXON 13R13 F13 2184delA FIG. 2. Login to comment

PMID: 18344710 [PubMed] Madore AM et al: "Distribution of CFTR mutations in Saguenay- Lac-Saint-Jean: proposal of a panel of mutations for population screening."

No. Sentence Comment

4 Results: Significant differences in allelic frequencies of common mutations (as ‚F508, 621 ϩ 1GϾT and A455E), and in percentage of covered allele with three or six mutations, were found in Saguenay-Lac-Saint-Jean compared to other regions. Login to comment
41 Three mutations are prevalent in the SLSJ population (‚F508, 621 ϩ 1GϾT, and A455E); according to data provided by the genetic counseling services and the Chicoutimi CF clinic, three other mutations are present in at least three different families (711 ϩ 1GϾT, 3199del6, and Y1092X). Login to comment
46 Similarly, the A455E mutation frequency is two to three times higher in the SLSJ population compared with the other Francophone population studied (P ϭ 0.004) and eight times higher than in the Anglophone and multiethnic population of Montreal (P ϭ 0.013). Login to comment
48 Altogether, the six mutations represent 95.89% of the CFTR allele of CF patients in the SLSJ population, whereas the proportions are 86.85, 85.27, and Table 2 Cystic fibrosis mutations present in the four populations studied Mutationa Allelic frequency (number of alleles [%]) Populationb 1 2 3 4 „F508 106 (62.35) 55 (72.37) 398 (72.36) 67 (57.78) 621 ؉ 1G>T 42 (24.71) 6 (7.89) 30 (5.45) 1 (0.85) A455E 12 (7.06) 2 (2.63) 14 (2.55) 1 (0.85) 3199del6 1 (0.59) 1 (1.32) 7 (1.27) 1 (0.85) 711 ؉ 1G>T 1 (0.59) 1 (1.32) 15 (2.73) 1 (0.85) Y1092X 1 (0.59) 1 (1.32) 5 (0.91) 0 R117C 2 (1.18) 0 0 0 ‚I507 1 (0.59) 2 (2.63) 10 (1.82) 0 L206W 1 (0.59) 1 (1.32) 9 (1.64) 0 R1158X 1 (0.59) 0 0 0 S489X 1 (0.59) 0 1 (0.18) 0 R553X 0 2 (2.63) 2 (0.36) 0 R334W 0 1 (1.32) 2 (0.36) 0 G542X 0 0 10 (1.82) 0 G85E 0 0 6 (1.09) 5 (4.24) N1303K 0 0 5 (0.91) 1 (0.85) IVS8-5T 0 0 4 (0.73) 0 W1282X 0 0 3 (0.55) 7 (5.93) R347P 0 0 1 (0.18) 2 (1.69) V520F 0 0 1 (0.18) 0 I1027T 0 0 1 (0.18) 0 R1066C/IVS 0 0 1 (0.18) 0 Q1313X 0 0 1 (0.18) 0 1898ϩ3GϾA 0 0 1 (0.18) 0 2183AAϾG 0 0 1 (0.18) 0 2951insA 0 0 1 (0.18) 0 G551D 0 0 0 2 (1.69) 1525-iG-A 0 0 0 2 (1.69) Y109C 0 0 0 1 (0.85) S549N 0 0 0 1 (0.85) 3154del1G 0 0 0 1 (0.85) UNKNOWN 1 (0.59) 4 (5.26) 20 (3.82) 25 (21.19) Number of alleles genotypedc 170 (100) 76 (100) 550 (100) 118 (100) a The six mutations included in the panels proposed are in bold. Login to comment
59 The three most common alleles in the SLSJ population are the ‚F508, 621 ϩ 1GϾT and A455E mutations. Login to comment
60 The frequency of the ‚F508 mutation is lower in the SLSJ population than in the other Francophones population (P ϭ 0.011) but the frequency of the 621 ϩ 1GϾT and A455E mutation is greater in this region than in any other region described here (P Ͻ 10-12 and P ϭ 0.004 for the Francophone populations, and P Ͻ 10-7 and P ϭ 0.013 for the Anglophone and multiethnic population, respectively). Login to comment
65 In the study of Rozen et al.,33 the authors also observed that the frequency for ‚F508 mutation was lower in SLSJ region (58.0%) than in the other regions of the PQ (71%) (P ϭ 0.047), and that subjects from the SLSJ region also have a higher 621 ϩ 1GϾT (23.2%) frequency than those of the remaining regions of the PQ (12.84%) (P ϭ 10-5 ).21,33 Four of our six most frequent mutations (‚F508, 621 ϩ 1GϾT, A455E, and 711 ϩ 1GϾT) are present in the ACMG- ACOG panel of 23 mutations, representing a detection rate of 94.71% in the SLSJ population. Login to comment
66 However, according to our results, a multimutation panel for carrier screening in the SLSJ region could include only the three principal mutations (‚F508, 621 ϩ 1GϾT, and A455E), covering a total of 94.12% of the CFTR alleles present in the SLSJ region (Fig. 3). Login to comment

PMID: 18470946 [PubMed] Berwouts S et al: "Evaluation and use of a synthetic quality control material, included in the European external quality assessment scheme for cystic fibrosis."

No. Sentence Comment

153 These very faint signals for wild-type R553X (c.1657C4T, p.Arg553X), wild-type R117H (c.350G4A, p.Arg117His), mutant G542X (c.1624G4T, p.Gly542X), and mutant A455E (c.1364C4A, p.Ala455Glu) signal were often not visible to the assessors on the copies of the raw data. Login to comment
157 ErrorTypes for the QCS in More Detail, for the LaboratoriesThat Used Only One Detection AssayÃ Genotype error Genotype Detection assay Number of labs Expected Reported Comment OLA-CFASR v2.0 1 R117 H hom ^ Correct on raw data INNO-LiPA CFTR36 1 R117 H hom R117 H het No signal for wt R117 H visible on copy of the raw data, could be very weak on original raw data INNO-LiPA CFTR36 1 R553X hom R553X het No signal for wt R553X visible on copy of the raw data, could be very weak on original raw dataI507del hom I507del/F508del Sequencing 2 R347 H hom ^ No complete raw data received Sequencing 1 I507del hom ^ No raw data received Additional mutation(s) reported Detection assay Number of labs Additional mutation(s) Comment OLA-CFASR v3.0 US 1 2184delAa hom Software called it INNO-LiPA CFTR36 3 A455E het (3labs), F508del (1lab) No signal for mut A455E visible on copy of the raw data, could be very weak on original raw data ARMS-ElucigeneTM CF29 3 2184delAa (3labs), R347P (3labs), 1717-1G4A (3labs), 3849110kbC4T (2labs) Cross reaction with 2183AA4Gb and R347 H and no full compatibility of MMQCI-CF-P1and ARMS method: no control bands visible ARMS-ElucigeneTM CF29 1CF-HT 1 2184delAa , R347P Cross reaction with 2183AA4Gb and R347H Sequencing 1 W1282X het, N1303 K het No raw data received ASPE-CFTR 4014 Tag-It 1 71111G4T het No raw data received Genotype error 1 additional mutation(s) reported Genotype Detection assay Number of labs Expected Reported Comment Additional mutation(s) Comment OLA-CFASR v3.0 EU 1 R117 H hom ^ No raw data received; probably 2183AA4Gb missed, but 2184delAa reported due to cross reaction 2184delAa hom No raw data received, probably due to cross-reaction with 2183AA4Gb 394delTTc hom 394delTTc het 2183AA4Gb hom ^ INNO-LiPA CFTR36 1 R553X hom I507del hom R553X het I507del/ F508del No signal for wt R553X visible on copy of the raw data, could be very weak on original raw data G542X het A455E het No signal for mut G542X and mut A455E visible on copy of the raw data, could be very weak on original raw data INNO-LiPA CFTR36 1 Italian regional 1 R553X hom R553X het No signal for wt R553X visible on copy of the raw data, could be very weak on original raw data Q552X het Misinterpretation: wt and mut signal for Q552X not visible, but this is a normal reaction pattern when R553X is hom present; the lab reported R553X het ARMS-ElucigeneTM CF29 1 I507del hom ^ No full compatibility of MMQCI- CF-P1 and ARMS method: no control bands R347P Cross-reaction with R347H2183AA4Gb hom ^ ÃIf the zygosity is not mentioned in the table, the laboratory did not report it. Login to comment
191 For example, reporting the weak bands for wild-type R553X (c.1657C4T, p.Arg553X) and R117 H (c.350G4A, p.Arg117His), mutant G542X (c.1624G4T, p.Gly542X) and A455E (c.1364C4A, p.Ala455Glu) seen by some of the laboratories using the INNO-LiPA assay could be explained in this respect. Login to comment
152 Finally, some laboratories using the INNO-LiPA assay obtained a very faint hybridization signal for the A445E (c.1364C4A, p.Ala455Glu) mutant probe, but a normal signal for the wild-type probe. Login to comment

PMID: 18474670 [PubMed] Guimbellot JS et al: "Role of oxygen availability in CFTR expression and function."

No. Sentence Comment

234 For example, the A455E mutation results in marginally reduced function of CFTR and clinically mild pulmonary disease, a later age at diagnosis, and a substantially improved prognosis (37). Login to comment

PMID: 18493878 [PubMed] Paranjape SM et al: "Atypical cystic fibrosis and CFTR-related diseases."

No. Sentence Comment

64 Determination of the transepithelial nasal potential difference has been beneficial in establishing a CF Table 1 Mutations, sites, and molecular consequences associated with either an atypical presentation of CF respiratory disease or pancreatic sufficiency or late-onset pancreatic insufficiency (http:// www.genet.sickkids.on.ca) Mutation Site Consequence Atypical presentation M1210I Exon 19 Met to Ile at 1210 S1455X Exon 24 Ser to Stop at 1455 1811+18G→A Intron 11 mRNA splicing defect L346P Exon 7 Leu to Pro at 346 Y161D Exon 4 Tyr to Asp at 161 R31C Exon 2 Arg to Cys at 31 I752S Exon 13 Ile to Ser at 752 2811G/T Exon 15 Sequence variation Pancreatic sufficiency or late-onset pancreatic insufficiency R600G Exon 13 Arg to Gly at 600 D1152H Exon 18 Asp to His at 1152 Y89C Exon 3 Tyr to Cys at 89 R117H Exon 4 Arg to His at 117 D110E Exon 4 Asp to Glu at 110 296 + 3insT Intron 2 mRNA splicing defect E217G Exon 6a Glu to Gly at 217 V392G Exon 8 Val to Gly at 392 N1088D Exon 17b Asn to Asp at 1088 S737F Exon 13 Missense 1716+1G→A Intron 10 mRNA splicing defect R334W Exon 7 Arg to Trp at 334 R347P Exon 7 Arg to Pro at 347 A455E Exon 9 Ala to Glu at 455 P574H Exon 12 Pro to His at 574 3850-3T→G Intron 19 mRNA splicing defect diagnosis in many atypical cases. Login to comment

PMID: 18535191 [PubMed] Adler AI et al: "Genetic determinants and epidemiology of cystic fibrosis-related diabetes: results from a British cohort of children and adults."

No. Sentence Comment

54 Genotypes associated with cystic fibrosis were coded into five established classes reflecting CFTR function of defective production, processing, regulation, conductance, and quantity of CFTR protein (12) as follows: I: G542X, R553X, W1282X, R1162X, 621-1G3T, 1717- 1G3 A, 1078⌬T, and 3659⌬C; II: ⌬F508, ⌬I507, N1303K, and S549N; III: G551Dand R560T; IV: R117H, R334W, G85E, and R347P; V: 3849ϩ5G3A, and A455E; and unknown: 711ϩIG3 T, 2184DA, and 1898ϩIG3 A. Login to comment

PMID: 18639722 [PubMed] Farrell PM et al: "Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report."

No. Sentence Comment

142 Recommended panel of CF-causing mutations Missense, deletion, stop mutations Splicing, frameshift mutations G85E I507del R560T 621ϩ1GϾT 2789ϩ5GϾA R117H F508del R1162X 711ϩ1GϾT 3120ϩ1GϾA R334W G542X W1282X 1717-1GϾA 3659delC R347P G551D N1303K 1898ϩ1GϾA 3849ϩ10kbCϾT A455E R553X 2184delA Revised from the mutation panel for population screening for CF developed by the ACMG.77 Additional or alternative mutations present at significant frequencies in an ethnic population served by an NBS program may be added. Login to comment

PMID: 18782298 [PubMed] Sharma N et al: "Identification and characterization of CFTR gene mutations in Indian CF patients."

No. Sentence Comment

42 CFTR mutations investigated by restriction analysis of PCR products were R334W (MspI), R347P (NcoI), A455E (AciI), 2789+5G-A (SSPI), R1162X (DdeI), and 3849+10kb C-T (HphI) (Gasparini et al., 1991; Dean et al., 1990; Kerem et al., 1990; Highsmith et al., 1990). Login to comment

PMID: 18810634 [PubMed] Sharma N et al: "Implication of the cystic fibrosis transmembrane conductance regulator gene in infertile family members of Indian CF patients."

No. Sentence Comment

41 CFTR mutations were investigated by restriction analysis of PCR products R334W (MspI), R347P (NcoI), A455E (AciI), 2789 ? Login to comment

PMID: 19092437 [PubMed] Moskowitz SM et al: "Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders."

No. Sentence Comment

56 Liver disease is second to pulmonary disease (plus organ transplantation complications) as a cause of mortality in CF (1.7% of deaths).26 Table 3 Core mutation panel carrier recommended by the ACMG for routine CF diagnostic testing and carrier screening of the general population7 Intronic mutations Exonic mutations Missense Nonsense In-Frame Deletion 621ϩ1GϾT G85E G542X ⌬I507 711ϩ1GϾT R117H R553X ⌬F508 1717-1GϾA R334W R1162X 1898ϩ1GϾA R347P W1282X 2184delA A455E 2789ϩ5GϾA G551D 3120ϩ1GϾA R560T 3659delC N1303K 3849ϩ10kbCϾT Endocrine manifestations of CF CF-related diabetes mellitus (CFRDM) may present in adolescence. Login to comment
98 For example, compound heterozygotes with ⌬F508/A455E have better pulmonary function than individuals who are homozygous for ⌬F508.10 In individuals with one or two R117H mutations, the severity of lung disease depends on the presence of a variation in the poly T tract of intron 8.44,45 Individuals with the 5T variant in cis configuration with the R117H mutation plus a second CFTR disease-causing mutation usually develop the lung disease of CF; but those individuals with the 7T variant in cis configuration with the R117H mutation plus a second CFTR disease-causing mutation have a highly variable phenotype, which can range from no symptoms to mild lung disease (Table 4).44,46 Because the A455E and R117H mutations are associated with pancreatic sufficiency, the less severe lung disease seen in individuals with these mutations could be the consequence of better nutritional status. Login to comment
104 The mechanism of partial penetrance of the 5T allele for CAVD is due to variation in the length of the adjacent TG tract (estimated at 60% in one study).50,51 Thus, interpretation of the disease implications of the 5T variant requires assessment of the number of TG repeats adjacent to the polythymidine tract.51 DIAGNOSIS AND TESTING Clinical phenotype Phenotypic features of CF include but are not limited to the following: ● Chronic suppurative sinopulmonary disease, with chronic coughandsputumproduction,chronicwheezeandairtrap- ping, obstructive lung disease on lung function tests, persistent colonization with pathogens commonly found in individuals with CF, chronic chest radiograph abnormalities, chronic pansinusitis, and/or digital clubbing Table 5 Proportion of CFTR genotypes detected in men with CAVD, based on pooled data4,47,57,116 Allele 1 Allele 2 Proportion (%)a 5T 5T 2 Other than 5T Other than 5T 26 5T Other than 5T 26 5T Wild type 8 Other than 5T Wild type 17 Wild type Wild type 22 a Percentages total to Ͼ100% because of rounding Table 4 CFTR genotype-phenotype correlations41,44,50,51,57,114-116 Allele 1 Allele 2 Range of phenotypes Classica Classic Classic ϾϾ nonclassic Milda Classic or mild Nonclassic Ͼ classic R117H/5T Classic or mild Nonclassic Ͼ classic R117H/7T Classic or mild Asymptomatic female or CAVD Ͼ nonclassic 5T/TG13 or TG12 Classic or mild CAVD or nonclassic CF ϾϾ asymptomatic carrier 5T/TG11 Classic or mild Asymptomatic Ͼ CAVD 7T or 9T Classic or mild Asymptomatic 7T or 9T 7T or 9T Asymptomatic a Classic refers to Class I, II, and III mutations (e.g., ⌬F508); mild refers to Class IV and V mutations (e.g., A455E) exclusive of R117H and 5T alleles (see Table 1). Login to comment

PMID: 19181743 [PubMed] Sharma N et al: "Heterogenous spectrum of CFTR gene mutations in Indian patients with congenital absence of vas deferens."

No. Sentence Comment

56 CFTR mutations investigated by restriction analysis of PCR products were R334W (MspI), R347P (NcoI), A455E (AciI), 2789 þ 5 . Login to comment

PMID: 19843100 [PubMed] Burgel PR et al: "Non-classic cystic fibrosis associated with D1152H CFTR mutation."

No. Sentence Comment

42 The CF genetic analysis panel used in France seeks for 32 mutations: G85E, 394delTT, 621+1G>T, 711+1G>T, R334W, R347P, R347H, 1078delT, 5T/7T/9T, A455E, F508del, I507del, V520F, 1717-1G>A, G542X, G551D, R553X, R560T, S549R (T>G), S549N, 1898+1G>A, 2183AA>G, 2184delA, 2789+5G>A, 3120+1G>A, R1162X, 3659delC, 3849+10kbC>T, W1282X, 3905insT, 3876delA, N1303K. Login to comment

PMID: 20059485 [PubMed] Dorfman R et al: "Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?"

No. Sentence Comment

64 Mutations in the CFTR gene grouped by clinical category Cystic fibrosis CFTR-related disease No disease T338I D614G L320V V920L L90S M470V H199R S1251N I203M G550R P111A I148T Q1291H R560K L1388Q L183I R170H I1027T S549R D443Y P499A L1414S T908N R668C S549N A455E E1401K Q151K G27E I1234L Y563N R347P C866R S1118C P1290S R75Q A559T V520F P841R M469V E1401G P67L G85E S50Y E1409K R933G G458V G178R Y1032C R248T I980K G85V V392G L973P L137H T351S R334W I444S V938G R792G R560T R555G L1339F D1305E P574H V1240G T1053I D58G G551D L1335P I918M F994C S945L L558S F1337V R810G D1152H G1247R P574S R766M D579G W1098R H949R F200I R352Q L1077P K1351E M244K L206W M1101K D1154G L375F N1303K R1066C E528D D110Y R347H R1070Q A800G P1021S S549K A1364V V392A damaging` (is supposed to affect protein function or structure) and 'probably damaging` (high confidence of affecting protein function or structure). Login to comment
57 PI prevalence and in silico prediction scores for 13 most frequent missense mutations identified in Canadian CF patients Mutation Total PI Total (PI + PS) PI prevalence Class PANTHER scorea POLYPHENa SIFTa p.R334W 1 9 0.11 CF-PS -7.4419 Possibly damaging 0.01 p.P67L 2 14 0.14 CF-PS -4.1736 Probably damaging 0 p.R347P 2 12 0.17 CF-PS -7.5259 Possibly damaging 0.01 p.R347H 1 5 0.20 CF-PS -6.8327 Possibly damaging 0 p.A455E 8 39 0.21 CF-PS -8.8641 Probably damaging 0 p.L206W 4 19 0.21 CF-PS -8.5817 Possibly damaging 0 p.P574H 4 7 0.57 CF-PI/PSb -8.1252 Probably damaging 0 p.G85E 15 24 0.63 CF-PI/PSb -7.3194 Possibly damaging 0 p.M1101K 22 33 0.67 CF-PI/PSb -5.8849 Probably damaging 0.01 p.R1066C 7 8 0.88 CF-PI -7.7424 Probably damaging 0 p.G551D 56 59 0.95 CF-PI -9.5654 Probably damaging 0 p.N1303K 47 49 0.96 CF-PI -9.7687 Probably damaging 0 p.V520F 7 7 1.00 CF-PI -7.1652 Benign 0 aPANTHER scores range from zero to negative values (maximum -12). Login to comment
122 However, it completely misclassified other well-established mutations with low PI prevalence scores (p.L206W, p.R334W, p.R347P and p.A455E). Login to comment
124 SIFT-generated low (deleterious) scores for missense mutations associated both with the highest (p.N1303K, p.G551D, p.V520F) and the lowest PI prevalence scores (p.A455E, p.P67L, p.L206W). Login to comment
127 While PolyPhen correctly classified the PI-CF mutations p.G551D and p.N1303K as 'probably damaging`, it misclassified the mild PS mutations p.A455E and p.P65L into the same category (Fig. S1c, supporting information online). Login to comment

PMID: 20393308 [PubMed] Chandrasekharan S et al: "Impact of gene patents and licensing practices on access to genetic testing for cystic fibrosis."

No. Sentence Comment

182 The ACMG specifically indicated that "Asian-Americans and Native Americans without significant Caucasian admixture should be informed of Table 1 Recommended core mutation panel for cystic fibrosis carrier screening in the general population Standard mutation panel R560T, ⌬F508a , R553Xb , R1162X, ⌬I507, 2184delA, G542X, G551Db , W1282X, N1303K, 621ϩ1G⌬T, R117H, 1717-1G⌬A, A455E, G85E, R334W, R347P, 711ϩ1G⌬T, 1898ϩ1G⌬A, 3849ϩ10kbC⌬T, 2789ϩ5G⌬A, 3659delC, and 3120ϩ1G⌬A Additional testable mutations I506Vc , I507Vc , F508Cc , and 5T/ 7T/9Td a University of Michigan/HSC Patent No. US 5,776,677. b Johns Hopkins University, Patent No. US 5,407,796. c Benign variants. Login to comment

PMID: 20494257 [PubMed] Dungan JS et al: "Carrier screening for cystic fibrosis."

No. Sentence Comment

102 However, in instances of a positive family history of affected individuals, but with no known mutation, further Table 2 Mutation panel recommended by ACOG and ACMG (listed in order of decreasing frequency in non-Hispanic Caucasian population) F508 del delI507 R347P R1162X G542X R553X 71111G>T 2184delA G551D R117H R560T 189811G>A 62111G>T 3849110kbC>T 3569delC R334W W1282X 1717À1G>T A455E 312011G>T N1303K 278915G>A G85E Data from Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Login to comment

PMID: 20551307 [PubMed] Da Paula AC et al: "Folding and rescue of a cystic fibrosis transmembrane conductance regulator trafficking mutant identified using human-murine chimeric proteins."

No. Sentence Comment

305 The different effects of K584E on CFTR processing and Cl-channel function are reminiscent of A455E and P574H, two CF mutations associated with a milder clinical phenotype (44). Login to comment
306 Although production of the mature forms of A455E and P574H was reduced and very much delayed, A455E had channel activity similar to and P574H had channel activity greater than that of WT-CFTR (44). Login to comment

PMID: 20657600 [PubMed] Giuliani R et al: "Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols."

No. Sentence Comment

58 INNO-LiPA CFTR19 INNO-LiPA CFTR17 INNO-LiPA CFTR Italian regional [delta]F508 621+1G>T 1259insA G542X 3849+10kbC>T 4016insT N1303K 2183AA>G 4382delA W1282X 394delTT 852del22 G551D 2789+5G> A R1162X D579G 1717-1G>A 3659delC G1244E R553X R117H G1349D CFTRdele2,3 (21 kb) R334W I502T [delta]I507 R347P L1065P 711+1G>T G85E R1158X 3272-26A>G 3905insT 1078delT T338I R560T A455E S549R(A>C) 1898+1G>A S1251N 2143delA 711+5G>A 991del5 I148T E60X D1152H 3199del6 3120+1G>A 2184delA 1898+3A>G, R1070Q Q552X Poli-T tract variations R1066H R347H 621+3A>G R334Q E217G Abbreviation: CFTR, cystic fibrosis transmembrane conductance regulator. Login to comment

PMID: 20923678 [PubMed] Ooi CY et al: "Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis."

No. Sentence Comment

55 PIP Scores for Common, Well-Defined CFTR Mutations Mutation Canadian Consortium for CF Genetic Studies Verona CF Centre Mutation classTotal PI Total PIϩPS PIP score Total PI Total PIϩPS PIP score 621ϩ1GϾT 96 96 1.00 4 4 1.00 I-III 711ϩ1GϾT 36 36 1.00 1 1 1.00 I-III R553X 24 24 1.00 9 9 1.00 I-III I507del 11 11 1.00 12 12 1.00 I-III G542X 74 75 0.99 22 22 1.00 I-III F508del 1276 1324 0.96 181 188 0.96 I-III 1717-1GϾA 20 21 0.95 23 24 0.96 I-III W1282X 19 20 0.95 2 2 1.00 I-III N1303K 45 48 0.94 30 31 0.97 I-III R1162X 12 13 0.92 21 22 0.95 I-III G551D 59 67 0.88 0 0 - I-III G85E 16 22 0.73 4 5 0.80 I-III A455E 18 37 0.49 0 0 - IV-V 2789ϩ5GϾA 6 16 0.38 3 11 0.27 IV-V R334W 1 10 0.10 0 0 - IV-V 3849ϩ10kbCϾT 2 22 0.09 0 1 0.00 IV-V R117H 1 25 0.04 0 0 - IV-V NOTE. Login to comment
66 PIP scores for "moderate" mutations that have an inconsistent effect on pancreatic phenotype (PS and PI), which include 2789 ϩ 5GϾA and A455E, were correctly classified as intermediate (0.38 and 0.59, respectively). Login to comment

PMID: 20932301 [PubMed] Green DM et al: "Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients."

No. Sentence Comment

74 For Pa, the hazard ratio Table 1 Classification of CFTR alleles Category Mutation Specific mutations Class I Defective Protein Synthesis (nonsense, frameshift, aberrant splicing) 1078delT, 1154 insTC, 1525-2A > G, 1717-1G > A, 1898+1G > A, 2184delA, 2184 insA, 3007delG, 3120+1G > A, 3659delC, 3876delA, 3905insT, 394delTT, 4010del4, 4016insT, 4326delTC, 4374+1G > T, 441delA, 556delA, 621+1G > T, 621-1G > T, 711+1G > T, 875+1G > C, E1104X, E585X, E60X, E822X, G542X, G551D/R553X, Q493X, Q552X, Q814X, R1066C, R1162X, R553X, V520F, W1282X, Y1092X Class II Abnormal Processing and Trafficking A559T, D979A, ΔF508, ΔI507, G480C, G85E, N1303K, S549I, S549N, S549R Class III Defective Channel Regulation/Gating G1244E, G1349D, G551D, G551S, G85E, H199R, I1072T, I48T, L1077P, R560T, S1255P, S549 (R75Q) Class IV Decreased Channel Conductance A800G, D1152H, D1154G, D614G, delM1140, E822K, G314E, G576A, G622D, G85E, H620Q, I1139V, I1234V, L1335P, M1137V, P67L, R117C, R117P, R117H, R334W, R347H, R347P, R347P/ R347H, R792G, S1251N, V232D Class V Reduced Synthesis and/or Trafficking 2789+5G > A, 3120G > A, 3272-26A > G, 3849+10kbC > T, 5T variant, 621+3A > G, 711+3A > G, A445E, A455E, IVS8 poly T, P574H was increased 3 fold for those with 'Minimal` function when compared to those with 'Residual` function. Login to comment

PMID: 21097845 [PubMed] Sheridan MB et al: "CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR."

No. Sentence Comment

15 Most PS-CF patients have two mutations in the coding regions of the CFTR gene.5 6 At least one mutation permits residual CFTR function, allowing the patient to escape the classic CF phenotype.7 8 While the 23 mutation ACMG panel includes several mutations frequently associated with PS-CF (eg, R117H [p.Arg117His], A455E [p.Arg455Glu], 2789+5G/A [c.2657+5G/A], and 3849+10kbC/T [c.3717+12191C/T]), it is not uncommon for a PS-CF patient to carry a rare CFTR mutation that is not present in the panel.9 Detection of less common mutations can be accomplished by use of extended mutation panels10 or by comprehensive analysis of the coding regions of the CFTR gene using scanning11e13 or DNA sequencing methods.14 Scanning techniques detect 85e99% of CFTR mutations15e17 while DNA sequencing has a higher sensitivity because it allows analysis of individual nucleotides.18 19 However, these techniques do not identify gene rearrangements and mutations in non-coding regions that affect splicing or expression of RNA transcripts. Login to comment

PMID: 21228336 [PubMed] Brown MB et al: "Low abundance of sweat duct Cl- channel CFTR in both healthy and cystic fibrosis athletes with exceptionally salty sweat during exercise."

No. Sentence Comment

114 Mutations tested in this panel were ⌬F508, R334W, S549N, 3659delC, ⌬I507, I347P, A559T, S1255X, 1898ϩ1GϾA, R347H, N1303K, 1898ϩ5GϾT, 3876delA, A455E, 394delTT, 2183GGϾA, 3905insT, 3120ϩ1GϾA, V520F, 2184delA, G85E, Y1092X, 711ϩ1GϾT, 2307insA, Y122X, S549R, M1101K, 1078delT, 2789ϩ5GϾA, G551D, G542X, 621ϩ1GϾT, R560T, W1282X, 1717-1 GϾA, 3849 ϩ 10KbCϾT, R553X, R117H, and R1162X. Login to comment

PMID: 21296036 [PubMed] Ivady G et al: "Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis."

No. Sentence Comment

33 The Elucigene CF29Tm v2 Kit is capable of detecting the following mutations: p.Asp1152His (c.3454 GNC), c.1585-1 GNA, p.Gly542X (c.1624 GNT), p.Trp1282X (c.3846 GNA), p.Asn1303Lys (c.3909 C NG), p.Phe508del (c.1521_ 1523delCTT), c.3717+12191 CNT, p.Leu88IlefsX22 (c.262_ 263delTT), c.489+1 GNT, p.Ser1251Asn (c.3752 GNA), p.Gly551Asp (c.1652 GNA), p.Arg117His (c.350 GNA), p.Arg1162X (c.3484 CNT), p.Arg334Trp (c.1000 CNT), p.Ala455Glu (c.1364 CNA), p.Lys684SerfsX38 (c.2051_ 2052delAAinsG), p.Lys1177SerfsX15 (c. Login to comment

PMID: 21354377 [PubMed] Geborek A et al: "Association between genotype and pulmonary phenotype in cystic fibrosis patients with severe mutations."

No. Sentence Comment

98 Class I Class II Class III Class IV Class V 1717-1 G-NA F508del G551D 297 C-NA 2789+5 G-NA 3659delC S945L R560T R117C 3849+10 kb CNT 394delTT R347P A455E R553X T 3381 3849+10 kb C-T 621+1 G-NT E60X G542X W79R W1282X decline of pulmonary function was more rapid in patients with pancreatic insufficiency, mainly class II mutations, compared to CF patients with normal pancreatic function [4]. Login to comment

PMID: 21388895 [PubMed] Baker MW et al: "Optimal DNA tier for the IRT/DNA algorithm determined by CFTR mutation results over 14 years of newborn screening."

No. Sentence Comment

75 CFTR mutationa Proportion of allele Frequency of allele (%) Cumulative detection (%)b F508del 137/214 64.02 92.52 3849+10KbCNT 6/214 2.80 92.52c G542X 5/214 2.34 94.39 N1303K 4/214 1.87 98.13 R117H 4/214 1.87 99.07 R553X 3/214 1.40 99.07 1717-1GNA 2/214 0.93 99.07 G551D 1/214 0.47 100 R347P 1/214 0.47 100 A455E 1/214 0.47 100 W1282X 1/214 0.47 100 621+1GNT 1/214 0.47 100 a The other 11 mutations in ACMG 23 mutation panel are G85E, 711+1GNT, R334W, I507del, R560T, 1898+1GNA, 2184delA, 2789+5GNA, 3120+1GNA, R1162X and 3659delC. Login to comment

PMID: 21474639 [PubMed] Rohlfs EM et al: "Cystic fibrosis carrier testing in an ethnically diverse US population."

No. Sentence Comment

65 The median fluorescent intensity was determined, and the presence or absence of mutant and wild-type alleles was evaluated from the ratio of the mutant signal to the wild-type signal for the following mutations: c.1155_1156dupTA, c.2657ϩ5GϾA, c.3717ϩ12191CϾT, p.A455E, p.D1152H, p.F508del, p.G542X, p.G551D, p.I507del, p.L206W, p.N1303K, p.R117H, p.W1282X, and c.54-5940_ 273ϩ10250del21kb. Login to comment

PMID: 21507732 [PubMed] de Nooijer RA et al: "Assessment of CFTR function in homozygous R117H-7T subjects."

No. Sentence Comment

120 In addition, the normal bioelectrical phenotype in the nasal epithelium of the R117H homozygous subjects contrasts with the elevated sodium absorption and minimal Cl-conductance reported in NPD measurements for CF patients carrying the A455E mutation [22]. Login to comment
128 5R.A. CBAVD in males [24], have distinct effects on the bioelectrical phenotype of the airways, ranging from normal (R117H) to severe (A455E). Login to comment
133 The lack of an intestinal bioelectrical phenotype in both R117H homozygous individuals may likewise result from intestine-specific rescue mechanisms but is also readily explained by the known insensitivity of the intestinal current measurements to a partial loss of CFTR function [30-32]. Login to comment
136 The R117H (and the A455E) CFTR mutants may therefore behave as borderline cases in which the homozygous expression is associated with a normal ICM pattern (≥20% residual CFTR conductance) whereas compound heterozygotes carrying a second more severe mutation (e.g. F508del) show a more variable residual CFTR Cl- current in the intestine ranging from normal to severely reduced, but not absent [24,33]. Login to comment
116 In addition, the normal bioelectrical phenotype in the nasal epithelium of the R117H homozygous subjects contrasts with the elevated sodium absorption and minimal Cl- conductance reported in NPD measurements for CF patients carrying the A455E mutation [22]. Login to comment
124 CBAVD in males [24], have distinct effects on the bioelectrical phenotype of the airways, ranging from normal (R117H) to severe (A455E). Login to comment

PMID: 21514289 [PubMed] Earley MC et al: "Implementation of the first worldwide quality assurance program for cystic fibrosis multiple mutation detection in population-based screening."

No. Sentence Comment

129 Allele Allele Allele Allele p.Gly85Glu G85E (0.26) p.Arg117His R117H (0.54) c.489+1 GNT 621+1 GNT (1.3) p.Phe508del F508del (66.31) p.Arg347Pro R347P (0.36) p.lle507del I507del (0.90) p.Gly551Asp G551D (1.93) c.2052delA 2184delA (0.15) c.1585-1 GNA 1717-1 GNA (0.44) p.Gly542X G542X (2.64) c.3528delC 3659delC (0.28) p.Asn1303Lys N1303K (1.27) p.Arg553X R553X (1.21) p.Arg560Thr R560T (0.30) p.Arg1162X R1162X (0.30) c.2657+5 GNA 2789+5 GNA (0.38) c.3717+12191 CNT 3849+10kbCNT (0.85) c.2988+1 GNA 3120+1 GNA (0.86) p.Trp1282X W1282X (2.20) p.Ala455Glu A455E (0.26) c.1766+1 GNA 1898+1 GNA (0.13) c.579+1 GNT 711+1 GNT (0.35) p.Arg334Trp R334W (0.37) c.54-5940 _273+10250del21kb CFTR dele2,3 p.Ser549Asn S549N (0.14) c.1584 GNA 1716 G→A c.2051_2052delAAinsG 2183AANG (0.1) c.3140-26ANG 3272-26ANG c.262_263delTT 394delTT p.Arg1066Cys R1066C (0.03) p.Arg1066His R1066H c.1022_1023insTC 1154insTC c.2989-1 GNA 3121-1 GNA c.(?_2989)_(3139_? Login to comment

PMID: 21538969 [PubMed] Ren CL et al: "Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome."

No. Sentence Comment

60 Infants in both groups received treatment with inhaled tobramycin if they had a positive Pa OP culture, and treatment in both groups was associated with eradication of TABLE 1-CFTR Gene Mutation Panel Used by New York CF NBS Program F508del I50e7del G542X G551D W1282X N1303K R553X 621þ1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711þ1G>T 1898þ1G>A 2184delA 1078delT 3849þ10kbC>T 2789þ5G>A 3659delC I148T 3120þ1G>A 3876delA V520F S549R S549N 3849þ4 A-G 3905insT R347H Reflex testing for 5T polymorphism is performed if R117H is detected. Login to comment
61 Infants in both groups received treatment with inhaled tobramycin if they had a positive Pa OP culture, and treatment in both groups was associated with eradication of TABLE 1- CFTR Gene Mutation Panel Used by New York CF NBS Program F508del I50e7del G542X G551D W1282X N1303K R553X 621þ1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711þ1G>T 1898þ1G>A 2184delA 1078delT 3849þ10kbC>T 2789þ5G>A 3659delC I148T 3120þ1G>A 3876delA V520F S549R S549N 3849þ4 A-G 3905insT R347H Reflex testing for 5T polymorphism is performed if R117H is detected. Login to comment

PMID: 21658632 [PubMed] Becq F et al: "Pharmacological therapy for cystic fibrosis: from bench to bedside."

No. Sentence Comment

56 Interestingly, Zielenski and Tsui [10] assigned A455E and P574H, two CF mutations associated with a milder clinical phenotype (pancreatic sufficiency) to Class V. Login to comment
58 Moreover, on reaching the cell surface A455E forms Cl-channels with open probability (Po), a measure of channel activity, similar to that of wild-type CFTR, whereas the Po of P574H exceeds that of wild-type CFTR [15]. Login to comment

PMID: 21658649 [PubMed] Bombieri C et al: "Recommendations for the classification of diseases as CFTR-related disorders."

No. Sentence Comment

323 Using biochemical (N) and functional (i and Po) data, the apical CFTR Cl- current generated by the CF-PI mutant p.F508del-CFTR and the CF-PS mutants p.R117H-, p.R334W-, p.R347P-, p.A455E- and p.P574H-CFTR were predicted [166,167]. Login to comment

PMID: 21762191 [PubMed] Ghorbel M et al: "Screening of DeltaF508 mutation and IVS8-poly T polymorphism in CFTR gene in Tunisian infertile men without CBAVD."

No. Sentence Comment

91 Table 2 Genotype frequencies of IVS8-polyT tract variants in infertile men and controls IVS8-polyT genotype frequencies (%) 5T/5T 7T/7T 9T/9T All infertile patients (n = 129) 1.55 69.76 4.65 Azoospermia (n = 57) 3.50 73.68 5.26 Oligospermia (n = 39) 0 71.79 5.12 Normospermia (n = 33) 0 60.60 3.03 Controls (n = 54) 0 59.25 3.70 Table 3 Microdeleted STSs and IVS8-polyT genotype in patients with Y chromosome microdeletions (n = 7) Number of microdeleted patients Y chromosome microdeleted AZF loci and STSs IVS8-polyT genotype in CFTR gene Azoospermia (n = 57) 1 AZFa (SY86) 9T/9T 1 AZFa (SY84) 7T/7T Oligospermia (n = 48) 1 AZFa (SY86) 9T/9T 1 AZFa (SY86) 7T/7T 1 AZFa (SY84) 7T/7T 1 AZFa + b (SY86 + SY134) 7T/7T Normospermia (n = 43) 1 AZFc (SY254) 7T/7T patients (Boucher et al., 1999); it also agrees with data reported by Tuerlings et al. (1998) showing no increase in 5T allele and in three frequent CFTR mutations (deltaF508, A455E and G542X) among patients with oligozoospermia. Login to comment

PMID: 9630075 [PubMed] Arduino C et al: "Congenital bilateral absence of vas deferens with a new missense mutation (P499A) in the CFTR gene."

No. Sentence Comment

52 Other missense mutations in this domain (A455E, P574H, G576A, S549N) have been found associated with a mild CF phenotype and their functional analysis in transfected cells revealed a low transport efficiency of the chloride channel and a reduced protein expression at the apical cell surface, which can explain the mild clinical phenotype (6). Login to comment

PMID: 9709387 [PubMed] Wilschanski M et al: "Pathology of pancreatic and intestinal disorders in cystic fibrosis."

No. Sentence Comment

97 Molecular consequences of cftr gene mutations Several classification systems have been developed in an attempt to define the large number of cftr gene mutations on 43 I =ON 4o0 o 00 4O0 40 40 I II 111 IV V Normal NOmAfl Missnso G542X Missmnse Missense Missense A455E Fremeshift AA dIeIIOn 05510 R117H Allerndve 39soTT AF508 spiRlng Spl$oeJunculon 3849t10kbC4T1717-1G-4A Figure 4 Molecular consequences of cystic fibrosis transmembrane conductance regulator mutations. Login to comment
119 Class V mutations result in reduced synthesis of normal functioning CFTR due to defective processing (A455E) or aberrant splicing at alternative sites (3849+10kbC-T). Login to comment
152 A small number of more Table 1 Classification of cystic fibrosis gene mutation as severe, mild or indeterminate with respect to pancreatic function Severe Mild Variable (classes 1, I/ or 111) (classes IV or V) (classes IV or V) AF508 R117H G85E 1148T R334W 2789+5G-*A G480C R347P G551D A455E R560T P574H N1303K 3849+1 Okb C-+T G542X G551S W1282X P5748 621 +1 G-T R352Q 1717-1G-T T3381 556delA Adapted from Ref 20 with permission recently described mutations [G85E and 278+5G-÷AI are less clearly determinant with respect to the pancreatic sufficient and pancreatic insufficient phenotypes. Login to comment

PMID: 9725922 [PubMed] Cohn JA et al: "Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis."

No. Sentence Comment

34 Pancreatograms were assessed for the severity of chronic pancreatitis according to published criteria by a reviewer who was unaware of the patients` histories (Table 1).19 DNA Studies We extracted DNA from blood samples20 and tested for 16 CFTR mutations - ∆F508, W1282X, R117H, 621+1(G→T), R334W, R347P, A455E, ∆I507, 1717¡1(G→A), G542X, S549N, G551D, R553X, R560T, N1303K, and 3849+10Kb(C→T) - using reverse dot blot strips (Roche Molecular Systems, Alameda, Calif.). Login to comment

PMID: 9842999 [PubMed] Cartault F et al: "Detection of more than 91% cystic fibrosis mutations in a sample of the population from Reunion Island and identification of two novel mutations (A309G, S1255L) and one novel polymorphism (L49L)"

No. Sentence Comment

15 Five have a frequency of 1% and above: AF508 (51%), Y122X (22.4%), 3120+ lG+A (7.7%), A455E (2.1%) and G551D (1.4%). Login to comment
26 The A455E has only been reported rarely in CF patients; its frequencyis higher than 1%in only two regions, in the Netherlands and in Saguenay Lac-Saint-Jean. Login to comment
30 Ten CFTR mutations identified in 69 CF families from Reunion Island Mutationa Exonlintron CF alleles Percentage Ama E.10 72 52 Y122X E.4 33 24 A455E E.9 3 2.2 G551D E.11 2 1.4 1717-1G-+A i.10 1 0.7 G542X E.ll 1 0.7 116ldelC E.7 1 0.7 A3G9G E.7 1 0.7 zag+ 5~-+A i.14b 1 0.7 3120tlG-A i.16 11 a Unknown mutations 12 8.7 aCystic Fibrosis Genetic Analysis Consortium: Web site: http // w.genet.sickkids.on.ca/cftr/ CFTR represents the missense mutation A309G (Fig. 1A). Login to comment

PMID: 9862818 [PubMed] Taylor CJ et al: "Chronic pancreatitis and mutations of the cystic fibrosis gene."

No. Sentence Comment

61 Reproduced with permission from Wilschanski et al.2 V Missense A455E Alternative splicing 3849+10kbC (f) IV Missense R117H (e) III Missense G551D (d) II Missense AA deletion ∆F508 (c) I Nonsense G542X Frameshift 394delTT Splice junction 1717-1G (b) Normal (a) T A Chronic pancreatitis and mutations of the cyctic fibrosis gene group.bmj.comon August 8, 2011 - Published bygut.bmj.comDownloaded from doi: 10.1136/gut.44.1.8 1999 44: 8-9Gut C J TAYLOR cystic fibrosis gene Chronic pancreatitis and mutations of the http://gut.bmj.com/content/44/1/8.full.html Updated information and services can be found at: These include: References http://gut.bmj.com/content/44/1/8.full.html#related-urls Article cited in: http://gut.bmj.com/content/44/1/8.full.html#ref-list-1 This article cites 4 articles, 2 of which can be accessed free at: service Email alerting box at the top right corner of the online article. Login to comment

PMID: 9877480 [PubMed] Fajac I et al: "Relationships between nasal potential difference and respiratory function in adults with cystic fibrosis."

No. Sentence Comment

148 In five CF patients carrying the A455E mutation associated with mild pulmonary disease, severe defects in airway bioelectrical properties were found [10]. Login to comment

PMID: 9917235 [PubMed] Ren CL et al: "Mutations of the cystic fibrosis gene and pancreatitis."

No. Sentence Comment

217 If CFTR mutations affect the sweat ducts, the function of CFTR in the lung will also be affected.4 The DF508/A455E genotype in particular is associated with elevated sweat chloride concentrations and delayed onset of pulmonary disease4 ; Sharer et al. did not screen for this mutation. Login to comment
231 An abnormal nasal potential difference is arguably a more reliable demonstrator of CFTR function than sweat testing,2 and indeed, patients with the 3849+10Kb (C→T) mutation may have normal sweat chloride concentrations but abnormal nasal-potential-difference properties.3 We did not test for the A455E mutation, since it does not seem to occur in our population.4 This mutation is associated with mild pulmonary disease, pancreatic sufficiency, and as far as we are aware, normal glucose tolerance.5 In our study, Patients 9 and 15 both had pancreatic insufficiency, with the latter also having insulin-dependent diabetes mellitus. Login to comment

PMID: 9922379 [PubMed] Schwiebert EM et al: "CFTR is a conductance regulator as well as a chloride channel."

No. Sentence Comment

108 A''half molecule`` of CFTR (TNR-CFTR) in which amino acids 836 through 1480 were eliminated (TMD-1, NBD1, mild mutation within NBD1, A455E, caused a small reduction in Cl0 channel function but did not affect cAMP stim-and R domains of CFTR intact) functioned in oocytes as a 9-pS single Cl0 channel similar to wild-type CFTR. Login to comment

PMID: 9950763 [PubMed] Clancy JP et al: "Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway."

No. Sentence Comment

251 For example, additional experiments in COS-7 cells have recently allowed us to identify two other surface-localized CFTR mutants (A455E and G1349D) that can functionally couple to A2B AR activation (11). Login to comment

PMID: 19883345 [PubMed] Christie LM et al: "Outcomes of a cystic fibrosis carrier testing clinic for couples."

No. Sentence Comment

72 This provides each individual with information on their carrier status, and accurate residual risks of 1 CFTR mutations tested for in individuals whose partner was a carrier of p.F508del* p.F508del p.F316leufsX p.I507del p.R347P p.G542X p.S1251N p.G551D p.E60X p.N1303K p.W1282X c.1585-1G>A p.D1152H p.R553X c.2988+1G>A c.489+G>T c.2657+5G>A p.R117H c.1766+1G>A p.R1162X c.579+1G>A c.3717+10kbC>T p.G85E p.R334W p.K684fs p.A455E p.I148T p.K684fs p.R560T p.T1176fs CFTR = gene encoding cystic fibrosis transmembrane conductance regulator. Login to comment

PMID: 21036675 [PubMed] Lay-Son G et al: "Cystic fibrosis in Chilean patients: Analysis of 36 common CFTR gene mutations."

No. Sentence Comment

50 Seven mutations had not been previously reported in the Chilean population (p.1078delT, pG85E, c.3120+1 GNA, c.711+1 GNT, p.R117H, p.A455E, and p.I148T). Login to comment
81 Mutation This study Rios et al. [4] Molina et al. [5] Repetto et al. [6] Perez et al. [13] CFGAC [2] (n=578) (%) (n=72) (%) (n=36) (%) (n=100) (%) (n=4102) (%) (n=43,849) (%) Chile Chile Chile Chile Latin-Americaa Worldwide Unknown 58.0 66.6 61.1 34.0 36.7 22.7 p.F508del 30.6 29.2 30.6 45.0 47.1 66.0 p.R334W 3.1 - - 2.0 0.8 0.1 p.G542X 2.4 0 8.3 7.0 5.0 2.4 c.3849+10Kb CNT 1.7 - - 3.0 0.3 0.2 p.R553X 1.2 4.2 0 1.0 0.4 0.7 p.R1162X 0.9 - - 2.0 1.0 0.3 p.1078delT 0.5 - - 0 b0.1 0.1 p.G85E 0.5 - - - 0.8 0.2 p.W1282X 0.2 - - 5.0 1.0 1.2 c.3120+1 GNA 0.2 - - - 0.3 - c.711+1 GNT 0.2 - - - 0.1 0.1 p.R117H 0.2 - - 0 b0.1 0.3 p.A455E 0.2 - - 0 0 0.1 p.I148T 0.2 - - - - - p.G551D 0 0 0 1.0 0.1 1.6 p.N1303K 0 0 0 0 1.8 1.3 c.621+1 GNT 0 - - 0 0.2 0.7 c.1717-1 GNA 0 - - 0 0.3 0.6 p.I507del 0 - - 0 0.2 0.2 p.R347P 0 - - 0 0 0.2 c.2789+5 GNA 0 - - - 0.2 0.1 c.1898+1 GNA 0 - - - 0.1 0.1 c.2184delA 0 - - - b0.1 0.1 p.S549N 0 - 0 - 0.1 0.1 c.3659delC 0 - - 0 0.1 0.1 p.R560T 0 - - - 0 0.1 c.1811+1.6Kb ANG 0 - - - 0.4 - c.2183AANG 0 - - 0 0.1 - p.S549R 0 - - - 0.1 - c.3272-26 ANG 0 - - - 0.1 - c.3199del6 0 - - - b0.1 - p.E60X 0 - - 0 0 - c.3905insT 0 - - - 0 - p.S1251N 0 - - 0 - - CFTRdele2,3 0 - - - - - p.R347H 0 - - - - - p.V520F 0 - - - - - p.Q552X 0 - - - - - c.394delTT 0 - - - - - c.711+1 GNA 0 - - - - - c.2143delT 0 - - - - - c.3876delA 0 - - - - - a Data from Chilean patients published in Rios et al., Molina et al., and Repetto et al. [4-6] included in this publication were excluded in this table to avoid repetition. Login to comment

PMID: 1375156 [PubMed] Bremer S et al: "Quantitative expression patterns of multidrug-resistance P-glycoprotein (MDR1) and differentially spliced cystic-fibrosis transmembrane-conductance regulator mRNA transcripts in human epithelia."

No. Sentence Comment

138 After screening for the Phe508 deletion (Kerem et al., 1989), most CFTR mutations were investigated by restriction analysis of PCR products (R334W, R347P, A455E, G551D, R553X, R1162X, W1282X) (Cutting et al., 1990; Dean et al., 1990; Gasparini et al., 1991; Kerem et al., 1990; Vidaud et al., 1990). Login to comment

PMID: 1717452 [PubMed] Shyamala V et al: "Structure-function analysis of the histidine permease and comparison with cystic fibrosis mutations."

No. Sentence Comment

159 A few mutations are located in the nucleotide-binding pocket, A455E,G458V, and P574H, and may be tolerated because they may have maintained partial activity, especially the two that are not located insites defined as critical for ATP binding by the HisPanalysis. Login to comment

PMID: 22859523 [PubMed] Quinton P et al: "beta-Adrenergic Sweat Secretion as a Diagnostic Test for Cystic Fibrosis."

No. Sentence Comment

42 DIAGNOSTIC CHARACTERISTICS OF PARTICIPANTS IN THE VALIDATION COHORT Group Age (yr) Sex Genotype Sweat Cl2 (mmol/L) Cholinergic b-Adrenergic Ratio b/Chol Healthy 38 M 2/2 15 64.45 72.79 1.13 Healthy 39 M 2/2 18 81.61 86.08 1.05 Healthy 54 F 2/2 29 48.90 47.30 0.97 Healthy 64 F 2/2 28 50.64 57.54 1.14 Healthy 54 F 2/2 11 68.63 52.30 0.76 Hetero. 64 M F508del/2 16 68.21 36.78 0.54 Hetero. 56 M F508del/2 53 82.44 59.57 0.72 Hetero. 27 F F508del/2 11 78.30 46.30 0.59 Hetero. 29 F F508del/2 16 65.63 26.13 0.40 Hetero. 51 F G551D/2 62 39.13 16.50 0.42 CFTR-RD CBAVD 41 M W1282X/5T 55 84.61 20.69 20.01 CFTR-RD CBAVD 52 M F508del/R117H (7T) 57 70.39 20.61 20.01 CFTR-RD CBAVD 41 M F508del/5T 40 68.00 22.29 20.03 CFTR-RD CBAVD 47 M G551D/R117H (7T) 57 65.93 10.08 0.15 CFTR-RD CBAVD 40 M L206W/W216C 42 67.80 17.00 0.25 CFTR-RD CBAVD 26 M 36599delC15T/7T 55 91.55 0.18 0.00 CFTR-RD Sinopulm 65 F F508del/c.876-9_876-6delGATT 51 74.30 32.20 0.43 CFTR-RD Sinopulm 39 F R764X/2 12 24.64 3.49 0.14 CFTR-RD Sinopulm 17 F 5T/2 50 52.95 14.24 0.27 CFPS 21 M F508del/2 97 46.19 0.56 0.01 CFPS 33 M F508del/3849110kbC.T 50 76.22 22.94 20.04 CFPS 58 M 71111G.T/A455E 72 70.19 23.06 20.04 CFPS 41 M G551D/3849110kbC.T 88 87.37 0.08 0.00 CFPS 54 F F508del/R117C 59 36.74 1.06 0.03 CFPS 23 F F508del/A455E 82 64.85 3.46 0.05 CFPS 30 F D1152H/D1152H 31 41.52 23.54 20.09 CFPS 55 F G551D/2 99 67.62 21.78 20.03 CFPS 42 F F508del/1002-2A.G 94 27.64 2.63 0.10 CFPS 46 F 3849110kbC.T/3849110kbC.T 53 24.43 21.16 20.05 CFPS 14 F R1162X/3849110kbC.T 46 50.19 20.49 20.01 CFPI 32 M F508del/F508del 108 73.93 1.41 0.02 CFPI 28 M F508del/F508del 84 95.13 3.45 0.04 CFPI 24 F F508del/F508del 109 60.48 4.06 0.07 CFPI 34 F F508del/F508del 115 79.24 0.99 0.01 CFPI 35 F F508del/F508del 87 79.79 23.02 20.04 CFPI 44 F F508del/F508del 112 80.60 1.23 0.02 CFPI 23 F F508del/G551D 90 45.80 0.80 0.02 Definition of abbreviations: CBAVD ¼ congenital bilateral absence of vas deference; CF ¼ cystic fibrosis; CFPI ¼ pancreatic-insufficient patients with CF; CFPS ¼ pancreatic-sufficient patients with CF; CFTR ¼ CF transmembrane regulator; CFTR-RD ¼ CFTR-related disorder; hetero ¼ heterozygotes; sinopulm ¼ chronic sinopulmonary disease. Login to comment
43 DIAGNOSTIC CHARACTERISTICS OF PARTICIPANTS IN THE VALIDATION COHORT Group Age (yr) Sex Genotype Sweat Cl2 (mmol/L) Cholinergic b-Adrenergic Ratio b/Chol Healthy 38 M 2/2 15 64.45 72.79 1.13 Healthy 39 M 2/2 18 81.61 86.08 1.05 Healthy 54 F 2/2 29 48.90 47.30 0.97 Healthy 64 F 2/2 28 50.64 57.54 1.14 Healthy 54 F 2/2 11 68.63 52.30 0.76 Hetero. 64 M F508del/2 16 68.21 36.78 0.54 Hetero. 56 M F508del/2 53 82.44 59.57 0.72 Hetero. 27 F F508del/2 11 78.30 46.30 0.59 Hetero. 29 F F508del/2 16 65.63 26.13 0.40 Hetero. 51 F G551D/2 62 39.13 16.50 0.42 CFTR-RD CBAVD 41 M W1282X/5T 55 84.61 20.69 20.01 CFTR-RD CBAVD 52 M F508del/R117H (7T) 57 70.39 20.61 20.01 CFTR-RD CBAVD 41 M F508del/5T 40 68.00 22.29 20.03 CFTR-RD CBAVD 47 M G551D/R117H (7T) 57 65.93 10.08 0.15 CFTR-RD CBAVD 40 M L206W/W216C 42 67.80 17.00 0.25 CFTR-RD CBAVD 26 M 36599delC15T/7T 55 91.55 0.18 0.00 CFTR-RD Sinopulm 65 F F508del/c.876-9_876-6delGATT 51 74.30 32.20 0.43 CFTR-RD Sinopulm 39 F R764X/2 12 24.64 3.49 0.14 CFTR-RD Sinopulm 17 F 5T/2 50 52.95 14.24 0.27 CFPS 21 M F508del/2 97 46.19 0.56 0.01 CFPS 33 M F508del/3849110kbC.T 50 76.22 22.94 20.04 CFPS 58 M 71111G.T/A455E 72 70.19 23.06 20.04 CFPS 41 M G551D/3849110kbC.T 88 87.37 0.08 0.00 CFPS 54 F F508del/R117C 59 36.74 1.06 0.03 CFPS 23 F F508del/A455E 82 64.85 3.46 0.05 CFPS 30 F D1152H/D1152H 31 41.52 23.54 20.09 CFPS 55 F G551D/2 99 67.62 21.78 20.03 CFPS 42 F F508del/1002-2A.G 94 27.64 2.63 0.10 CFPS 46 F 3849110kbC.T/3849110kbC.T 53 24.43 21.16 20.05 CFPS 14 F R1162X/3849110kbC.T 46 50.19 20.49 20.01 CFPI 32 M F508del/F508del 108 73.93 1.41 0.02 CFPI 28 M F508del/F508del 84 95.13 3.45 0.04 CFPI 24 F F508del/F508del 109 60.48 4.06 0.07 CFPI 34 F F508del/F508del 115 79.24 0.99 0.01 CFPI 35 F F508del/F508del 87 79.79 23.02 20.04 CFPI 44 F F508del/F508del 112 80.60 1.23 0.02 CFPI 23 F F508del/G551D 90 45.80 0.80 0.02 Definition of abbreviations: CBAVD &#bc; congenital bilateral absence of vas deference; CF &#bc; cystic fibrosis; CFPI &#bc; pancreatic-insufficient patients with CF; CFPS &#bc; pancreatic-sufficient patients with CF; CFTR &#bc; CF transmembrane regulator; CFTR-RD &#bc; CFTR-related disorder; hetero &#bc; heterozygotes; sinopulm &#bc; chronic sinopulmonary disease. Login to comment

PMID: 22390181 [PubMed] Grzegorczyk V et al: "Management of male infertility due to congenital bilateral absence of vas deferens should not ignore the diagnosis of cystic fibrosis."

No. Sentence Comment

6 CFTR molecular testing detected two mutations F508del and A455E corresponding to a cystic fibrosis genotype. Pneumological evaluation revealed a severe obstructive respiratory disease, bronchiectasis and high sweat chloride levels. Login to comment
29 CFTR molecular testing detected two mutations, F508del and A455E (Pr. C. Ferec, Brest University Hospital) corresponding to a CF genotype. Pneumological evaluation confirmed the diagnosis of CF with a severe obstructive respiratory disease, bronchiectasis and high sweat chloride levels. Login to comment
49 Some genotypes had been described in patients with moderate or late CF, such as those with F508del/L206W, F508del/D1152H, F508del/A455E like in our patient. Login to comment
51 A455E mutation is a missense mutation and belongs to class V mutation. Login to comment
54 A relationship has been described between the A455E mutation and milder lung disease in patients with CF. Login to comment
55 Patients with the A455E mutation had significantly better lung function and less pancreatic insufficiency than the F508del homozygotes (Gan et al., 1995) and are generally diagnosed at older age than matched F508del homozygotes. Login to comment
56 Mild symptoms of CF are most likely associated with the presence of A455E mutation because all of the A455E compound heterozygotes had a severe mutation in the second allele like our proband (Gan et al., 1995). Login to comment
57 These data were confirmed by De Braekeleer et al. (1997) who showed that pulmonary problems were the leading clinical feature at diagnosis with a mean sweat chloride concentration lower among the A455E heterozygotes. Login to comment
58 Moreover, a lower mortality rate was also reported in patients with F508del/ A455E than in F508del homozygotes (9.1% vs 21.2%) confirming the evidence that the A455E mutation is associated with a milder form of CF and a better prognosis. Login to comment

PMID: 22627569 [PubMed] De Bie I et al: "Report on the p.Ser489X (p.Ser489*) CFTR mutation, a variant with severe associated phenotype and high prevalence in a Quebec French-Canadian cystic fibrosis patient population."

No. Sentence Comment

4 In this population, three Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations account for ~94% of disease alleles, namely p.Phe508del (p.F508del; [delta] F508, c.1521_1523delCTT), 621+1G>T (c.489+1G>T), and p.Ala455Glu (p.A455E; c.1364C>A).3,4 Molecular CFTR testing is usually performed to confirm a clinical diagnosis of CF, to determine carrier status in individuals at risk, or to corroborate results of newborn screening. Login to comment
62 None of the CF probands of our cohort identified as originating from the SLSJ region were found to be carriers of the p.Ser489X variant, whereas Madore et al.4 had reported this variant in one of their SLSJ CF patients, with an estimated allele frequency of 0.59% for this population.The allele frequencies of two of the three most common SLSJ CFTR mutations, namely p.Phe508del and p.Ala455Glu, are similar in our cohort to those reported by Madore et al.4 for this population. Login to comment
55 Frequencies of CFTR disease-causing alleles in the French-Canadian cystic fibrosis patient population CFTR variant All variants p.Phe508del 621+1G>T 711+1G>T p.Ala455Glu p.Ser489X p.Arg334Trp 3199del6 p.Gly542X p.Gly85Glu p.Ile507del FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ FC SLSJ Number of CF chromosomes 1712 172 1321 116 143 29 61 1 51 13 12 0 9 0 8 2 6 1 5 1 4 1 % Of total CF chromosomes 100.00 100.00 77.16 67.44 8.35 16.86 3.56 0.58 2.98 7.56 0.70 0.00 0.53 0.00 0.47 1.16 0.35 0.58 0.29 0.58 0.23 0.58 CF, cystic fibrosis; FC, French-Canadian; SLSJ, Saguenay-Lac-St-Jean. Login to comment
61 None of the CF probands of our cohort identified as originating from the SLSJ region were found to be carriers of the p.Ser489X variant, whereas Madore et al.4 had reported this variant in one of their SLSJ CF patients, with an estimated allele frequency of 0.59% for this population.The allele frequencies of two of the three most common SLSJ CFTR mutations, namely p.Phe508del and p.Ala455Glu, are similar in our cohort to those reported by Madore et al.4 for this population. Login to comment

PMID: 22658665 [PubMed] Ooi CY et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis."

No. Sentence Comment

847 Total PI Total PI+PS PIP score 621+1G>T 96 96 1.00 Classes I - III 711+1G>T 36 36 1.00 Classes I - III R553X 24 24 1.00 Classes I - III I507del 34 34 1.00 Classes I - III G542X 74 75 0.99 Classes I - III F508del 1276 1324 0.96 Classes I - III 1717-1G>A 20 21 0.95 Classes I - III W1282X 19 20 0.95 Classes I - III N1303K 45 48 0.94 Classes I - III R1162X 12 13 0.92 Classes I - III G551D 59 67 0.88 Classes I - III G85E 16 22 0.73 Classes I - III A455E 18 37 0.49 Classes IV - V 2789+5G>A 6 16 0.38 Classes IV - V R334W 1 10 0.10 Classes IV - V 3849+10kbC>T 2 22 0.09 Classes IV - V R117H 1 25 0.04 Classes IV - V Mutation Canadian Consortium for CF Genetic Studies Mutation class The PIP score for a specific mutation is the ratio between the pancreatic insufficient patients carrying the mutation (Total PI) and all pancreatic insufficient and sufficient patients (Total PI+PS) carrying the same mutation in a homozygous state or heterozygous in a combination with a severe mutation such as F508del, G551D or a Class I mutation. Login to comment
855 CFTR mutation Total PI Total PI + PS PIP score CFTR mutation Total PI Total PI + PS PIP score 621+1G>T 96 96 1.00 G542X 74 75 0.99 711+1G>T 36 36 1.00 F508del 1276 1324 0.96 I507del 34 34 1.00 1717-1G>A 20 21 0.95 R553X 24 24 1.00 W1282X 19 20 0.95 Q493X 11 11 1.00 N1303K 45 48 0.94 S489X 11 11 1.00 R1162X 12 13 0.92 1154insTC 10 10 1.00 Y1092X 12 13 0.92 3659delC 9 9 1.00 I148T 10 11 0.91 CFTRdele2 7 7 1.00 V520F 9 10 0.90 4016insT 7 7 1.00 G551D 59 67 0.88 E60X 7 7 1.00 L1077P 5 6 0.83 R560T 7 7 1.00 R1066C 5 6 0.83 R1158X 7 7 1.00 2184insA 9 12 0.75 3905insT 6 6 1.00 2143delT 3 4 0.75 I148T;3199del6 5 5 1.00 1161delC 3 4 0.75 2183AA>G 5 5 1.00 3120+1G>A 3 4 0.75 1898+1G>A 5 5 1.00 S549N 3 4 0.75 2347delG 4 4 1.00 G85E 16 22 0.73 Q1313X 3 3 1.00 R117C 2 3 0.67 Q220X 3 3 1.00 M1101K 19 30 0.63 2184delA 3 3 1.00 P574H 3 5 0.60 1078delT 3 3 1.00 474del13BP 1 2 0.50 L1254X 3 3 1.00 R352Q 1 2 0.50 E585X 3 3 1.00 Q1291H 1 2 0.50 3876delA 2 2 1.00 A455E 18 37 0.49 S4X 2 2 1.00 R347P 6 15 0.40 R1070Q 2 2 1.00 2789+5G>A 6 16 0.38 F508C 2 2 1.00 L206W 6 18 0.33 DELI507 2 2 1.00 IVS8-5T 4 16 0.25 Q1411X 2 2 1.00 3272-26A>G 1 4 0.25 365-366insT 2 2 1.00 R334W 1 10 0.10 R709X 2 2 1.00 3849+10kbC>T 2 22 0.09 1138insG 2 2 1.00 P67L 1 14 0.07 CFTRdele2-4 2 2 1.00 R117H 1 25 0.04 3007delG 2 2 1.00 R347H 0 5 0.00 Q814X 2 2 1.00 G178R 0 3 0.00 394delTT 2 2 1.00 E116K 0 2 0.00 406-1G>A 2 2 1.00 875+1G>C 0 2 0.00 R75X 2 2 1.00 V232D 0 2 0.00 CFTRdel2-3 2 2 1.00 D579G 0 2 0.00 E193X 2 2 1.00 L1335P 0 2 0.00 185+1G>T 2 2 1.00 Mild mutations (based on PIP scores) are shaded in gray. Login to comment

PMID: 22892530 [PubMed] Sobczynska-Tomaszewska A et al: "Newborn screening for cystic fibrosis: Polish 4 years' experience with CFTR sequencing strategy."

No. Sentence Comment

57 Mutations D537N and P731L have not been Period of NBS CF Method The most frequent mutations in Polish population under analysis September 2006 - December 2007 Estonia Asper Biotech assay E60X, G85E, 394delTT, R117H, R117P, R117L, I148T, 621G>A, 711+1G>T, 711+5G>A, 1078delT, R334W, R347H, R347P, R347L, IVS8-T, A455E, I507del, F508del, 1717-1G>A, G542X, p.G551D, Q552X, R553X, R553G, R560T, R560K, 1898+1G>A, 1898+1G>T, 1898+1G>C, 2143delT, 2184delA, 2183AA>G, 2789+5G>A, 3120+1G>A, 3199del6, 3272-26A>G, R1162X, 3659delC, 3849+10kbC>T, 3905insT, S1235R, S1251N, W1282X, W1282C, N1303K, CFTRdele2,3 January 2007 - June 2009 Sanger sequencing of exons: 4, 7, 10, 11, 13, 21, fragment of intron 19 F508del, CFTRdele2,3, 3849+10kbC>T, R117H+IVS8-T*, R334W, R347P, 1717-1G>A, G542X, R553X, K710X, 2184insA, 2143delT, 2183AA>G, N1303K July 2009 - currently Sanger sequencing of exons: 7, 10, 11, 13, 17b, 20, 21, fragment of intron 19 F508del, CFTRdele2,3, 3849+10kbC>T, R334W, R347P, 1717-1G>A, G542X, R553X, K710X, 2184insA, 2143delT, 2183AA>G, N1303K, 3272-26A>G**, W1282X** * removed from DNA analysis since July 2009 , **added into DNA analysis since July 2009 Figure 1 NBS CF in Poland. Login to comment

PMID: 22581207 [PubMed] Krulisova V et al: "Prospective and parallel assessments of cystic fibrosis newborn screening protocols in the Czech Republic: IRT/DNA/IRT versus IRT/PAP and IRT/PAP/DNA."

No. Sentence Comment

81 According to the protocol, this result indicated the sequencing of the Table 1 Parallel comparison of CF NBS protocols IRT/DNAa /IRT IRT/PAP IRT/PAP/DNAa Newborns screened (N) 106,522 106,522 106,522 IRT positives (N; %) 1,158 (1.09) 3,155 (2.96) 3,155 (2.96) PAP positives (N; %) - 260 (0.24) 260 (0.24) Median age (range) at the availability of DNA-testinga results (days) 36 (9-222b ) - 36 (9-222b ) 1 and/or 2 CF mutations detected (N; %) 76 (0.07) - 27 (0.03) Recalled newborns for repeated IRT examination (N; %) 47 (0.04) - - Positive CF NBS (N; %) 123 (0.12) 260 (0.24) 27 (0.03) Positive IRT in newborns recalled for repeated examination (N) 1 - - ST indicated (N; %) 77 (0.07) 260 (0.24) 27 (0.03) ST carried out (N; % of indicated ST) 72c (93.51) 204c (78.46) 24c (88.89) CF carriers (N) 55 - 12 Prevalence of CF carriers 1 in 21 - 1 in 22 Diagnosed CF patients (N) 19 16 15 False positives based on performed ST (N; % of all cases screened) 99d (0.09) 188 (0.18) 9 (0.01) Newborns with equivocal diagnosis [F508del/R117H-IVS-8 T(7) and ST<30 mmol/L; N] 2 - 0 False negatives (N) 2 5 6 Total of CF patients detected (N) 21e Median age (range) at diagnosis (days) 36 (9-57)e CF prevalence 1 in 5,072e Sensitivity (TP/TP+FN) 0.9048 0.7619 0.7142 Specificity (TN/TN+FP) 0.9991 0.9982 0.9999 PPV (TP/TP+FP) 0.1610 0.0784 0.625 N number, % of all cases screened, TP true positives, FN false negatives, TN true negatives, FP false positives, PPV positive predictive value, ST sweat test a CF-causing mutations covered by Elucigene assays ("legacy" nomenclature) with the CF-EU1Tm accounting for: p.Arg347Pro (R347P), c.2657+ 5G>A (2789+5G>A), c.2988+1G>A (3120+1G>A), c.579+1G>T (711+1G>T), p.Arg334Trp (R334W), p.Ile507del (I507del), p.Phe508del (F508del), c.3718-2477C>T (3849+10kbC>T), p.Phe316LeufsX12 (1078delT), p.Trp1282X (W1282X), p.Arg560Thr (R560T), p.Arg553X (R553X), p.Gly551Asp (G551D), p.Met1101Lys (M1101K), p.Gly542X (G542X), p.Leu1258PhefsX7 (3905insT), p.Ser1251Asn (S1251N), c.1585-1G>A (1717-1G>A), p.Arg117His (R117H), p.Asn1303Lys (N1303K), p.Gly85Glu (G85E), c.1766+1G>A (1898+1G>A), p.Lys684AsnfsX38 (2184delA), p.Asp1152His (D1152H), c.54-5940_273+10250del (CFTRdele2,3), p.Pro67Leu (P67L), p.Glu60X (E60X), p.Lys1177SerfsX15 (3659delC), c.489+1G>T (621+1G>T), p.Ala455Glu (A455E), p.Arg1162X (R1162X), p.Leu671X (2143delT), c.1210-12T[n] (IVS8-T(n) variant), including additional mutations in the CF-EU2Tm : p.Gln890X (Q890X), p.Tyr515X (1677delTA), p.Val520Phe (V520F), c.3140-26A>G (3272-26A>G), p.Leu88IlefsX22 (394delTT), p.Arg1066Cys (R1066C), p.Ile105SerfsX2 (444delA), p.Tyr1092X (C>A) (Y1092X(C>A)), p.Arg117Cys (R117C), p.Ser549Asn (S549N), p.Ser549ArgT>G (S549R T>G), p.Tyr122X (Y122X), p.Arg1158X (R1158X), p.Leu206Trp (L206W), c.1680-886A>G (1811+1.6kbA>G), p.Arg347His (R347H), p.Val739TyrfsX16 (2347delG) and p.Trp846X (W846X) b failed DNA isolation from DBS, including repetition of DNA-testing c deceased patient or non-compliance with referrals (five CF carriers in IRT/DNA/IRT, 56 newborns in IRT/PAP, three CF carriers in IRT/PAP/DNA) d comprising newborns with repeated IRT (47 newborns) e aggregate data from all protocols entire CFTR coding region in both newborns, and led to the identification of p.Ile336Lys (I336K) and p.Glu1104Lys (E1104K) mutations. Login to comment

PMID: 22302635 [PubMed] Cornel MC et al: "Improving test properties for neonatal cystic fibrosis screening in the Netherlands before the nationwide start by May 1st 2011."

No. Sentence Comment

69 This protocol was expected to identify 25 CF patients on an annual basis, additional to four infants already diagnosed because of meconium ileus (Health Council of 1 Using the LiPA test (INNO-LiPA CFTR 19 en INNO-LiPA CFTR 17+Tn; Innogenetics, Gent, Belgium) the following CFTR mutations can be detected: exon 2-3del (21 kb), 394delTT, E60X, G85E, R117H, 621+1G>T, 711+1G>T, 711+5G>A, 1078delT, R334W, R347P, A455E, I507del, F508del, 1717-1G>A, G542X, G551D, Q552X, R553X, R560T, 1898+1G>A, 2143delT, 2183AA>G, 2184delA, 2789+5G>A, 3120+1G>A, 3199del6, 3272-26A>G, 3659delC, R1162X, 3849+10kbC>T, 3905insT, S1251N, W1282X en N1303K. Login to comment
70 This test also identifies the CFTR polymorphism Tn in intron 8 which is important in cases where the mutation R117H is detected. Login to comment

PMID: 21999194 [PubMed] Agarwal R et al: "Link between CFTR mutations and ABPA: a systematic review and meta-analysis."

No. Sentence Comment

56 (1996)[30] 11ABPA53chronic bronchitis Asthma,pulmonaryinfiltrates,CB, immediateAfskintestpositivity,totalIgE >1000ngml)1 ,positiveAfprecipitins, elevatedAfIgG/IgE,bloodeosinophilia, sweatchloride<40mmoll)1 /(United States) BothgroupssixmutationsF508del, G542X,GS51D,R553X,W1282X andN1303K;ninemoremutations inABPA:R117H,R347P,R347H, R334W,A455E,G551S, 2789+5G>A,D1152H,and 3849+10kbC>T ReverseASOanalysis andDGGEwithDNA sequencing 1patientcarried2CF (F508del;R347H)and5 carried1CF(4F508del; 1R117H).Mutationsseenin 6/11ABPAvs.1/53 controls Aronetal. Login to comment
59 (2002)[33] 31ABPAHealthycontrols (n=34) Asthma(n=51) Asthma,positiveSPTtoAf,totalIgE >1000ngml)1 ,elevatedAf-IgE,positive precipitinstoAf,bloodeosinophilia >350ll)1 ,pulmonaryinfiltratesonCXR orCBonCT/(NewZealand) 16CFmutations-F508del,I507del, R117H,W1282X,621+1G>T, R334W,R347P,A455E, 1717-1G>A,G542X,5549N, G551D,R553X,R560T,N1303Kand 3849+10kbC>T ASOhybridisationand DGGEwithDNA sequencing 4/31(F508del[n=3], R117H[n=1])vs.2/51 asthma(F508del[n=1], R117H[n=1])vs.1/34 healthycontrols ABPA,allergicbronchopulmonaryaspergillosis;ARMS,amplificationrefractorymutationsystem;ASO,allele-specificoligonucleotide;CB,centralbronchiectasis;CFTR,cysticfibrosis transmembraneconductanceregulator;DGGE,denaturinggradientgelelectrophoresis;OR,oddsratio CFTRmutationclass(classI--1717-1G>A,R1162X,G542X;classII--F508del,N1303K;classIV--R347H,R117H). Login to comment

PMID: 22468138 [PubMed] Elliott AM et al: "Rapid detection of the ACMG/ACOG-recommended 23 CFTR disease-causing mutations using ion torrent semiconductor sequencing."

No. Sentence Comment

26 Amplicons were then pooled together in equimolar concentrations and purified using the T A B L E 1 Data Generation from Three PGM Runs Run Total number of reads Total bases (Mbp) AQ17 total bases (Mbp) AQ17 avg. read length CF WT 101,211 8.5 6.5 68 CF 23 pooled mutants 222,247 18.6 12.52 64 CF mutant 135,000 11.7 8.8 72 T A B L E 2 CFTR Variant Coverage, Mutant Read Percentage, and Base-Call Accuracy from a WT Library Using PGM Sequencing Variant cDNA position Coverage Mutant read % Accuracy/base G85E c.254G Ͼ A 408 0 99.5 R117H c.350G Ͼ A 3627 0 99.9 621 ϩ 1G Ͼ T c.489 ϩ 1G Ͼ T 245 0 99.6 711 ϩ 1G Ͼ T c.579 ϩ 1G Ͼ T 2660 0 99.9 R334W c.1000C Ͼ T 5419 0 99.7 R347P c.1040G Ͼ C 3562 0 99.4 A455E c.1364C Ͼ A 10,340 0 99.9 ⌬I507 c.1519_1521delATC 6507 0 98.6 ⌬F508 c.1521_1523delCTT 6507 0 99.4 1717-1G Ͼ A c.1585-1G Ͼ A 2086 0 99.2 G542X c.1624G Ͼ T 854 0 97.8 G551D c.1652G Ͼ A 3901 0 99 R553X c.1657C Ͼ T 3915 0 99.9 R560T c.1679G Ͼ C 3924 0 99.6 1898 ϩ 1G Ͼ A c.1766 ϩ 1G Ͼ A 1793 0 97.6 2184delAa c.2052delA 2001 35% 63.6 2789 ϩ 5G Ͼ A c.2657 ϩ 5G Ͼ A 293 0 100 3120 ϩ 1G Ͼ A c.2988 ϩ 1G Ͼ A 2408 0 100 R1162X c.3484C Ͼ T 9610 0 98.1 3659delC c.3528delC 9271 0 100 3849 ϩ 10kbC Ͼ T c.3717 ϩ 12191C Ͼ T 10,157 0 99.9 W1282X c.3846G Ͼ A 4789 0 95.6 N1303K c.3909C Ͼ G 3236 0 99.5 a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not detected accurately as a result of homopolymer-length sequencing errors. Login to comment
67 For this data set, the PGM 314 chip output was 18.6 Mbp, with ϳ67% aligning to the CFTR T A B L E 3 PGM CFTR Variant Coverage and Mutant Read Percentage from a Pooled Mutant Library Representing All 23 ACMG/ACOG Mutations Variant cDNA position Coverage Mutant read % Predicted read % Genotype G85E c.254G Ͼ A 93 33 50 Het R117H c.350G Ͼ A 6228 39 50 Het 621 ϩ 1G Ͼ T c.489 ϩ 1G Ͼ T 1243 46 50 Het 711 ϩ 1G Ͼ T c.579 ϩ 1G Ͼ T 1352 29 50 Het R334W c.1000C Ͼ T 13,284 8 25 Het R347P c.1040G Ͼ C 9454 27 25 Het A455E c.1364C Ͼ A 19,527 43 50 Het ⌬I507 c.1519_1521delATC 15,587 14 25 Het ⌬F508 c.1521_1523delCTT 15,587 68 50 Homo 1717-1G Ͼ A c.1585-1G Ͼ A 3584 36 50 Het G542X c.1624G Ͼ T 610 41 50 Het G551D c.1652G Ͼ A 6714 16 17 Het R553X c.1657C Ͼ T 6670 15 17 Het R560T c.1679G Ͼ C 6395 22 17 Het 1898 ϩ 1G Ͼ A c.1766 ϩ 1G Ͼ A 3293 49 50 Het 2184delAa c.2052delA 2256 63 50 Het 2789 ϩ 5G Ͼ A c.2657 ϩ 5G Ͼ A 1765 54 50 Het 3120 ϩ 1G Ͼ A c.2988 ϩ 1G Ͼ A 7447 40 50 Het R1162X c.3484C Ͼ T 19,060 54 50 Het 3659delC c.3528delC 28,321 30 50 Het 3849 ϩ 10kbC Ͼ T c.3717 ϩ 12191C Ͼ T 27,102 46 50 Het W1282X c.3846G Ͼ A 9219 48 50 Het N1303K c.3909C Ͼ G 4842 49 50 Het a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
86 Using samples characterized previously, we analyzed the PGM`s data out- T A B L E 4 PGM CFTR Variant Coverage and Mutant Read Percentage from an Individual Harboring Two Disease-Causing CFTR Mutations Variant cDNA position Coverage Mutant read % G85E c.254G Ͼ A 237 0 R117H c.350G Ͼ A 3774 0 621 ϩ 1G Ͼ T c.489 ϩ 1G Ͼ T 936 0 711 ϩ 1G Ͼ T c.579 ϩ 1G Ͼ T 2018 0 R334W c.1000C Ͼ T 10,899 0 R347P c.1040G Ͼ C 7720 0 A455E c.1364C Ͼ A 14,525 0 ⌬I507 c.1519_1521delATC 8855 0 ⌬F508 c.1521_1523delCTT 8855 47 1717-1G Ͼ A c.1585-1G Ͼ A 2216 0 G542X c.1624G Ͼ T 2035 41 G551D c.1652G Ͼ A 4581 0 R553X c.1657C Ͼ T 4545 0 R560T c.1679G Ͼ C 4774 0 1898 ϩ 1G Ͼ A c.1766 ϩ 1G Ͼ A 2702 0 2184delAa c.2052delA 2837 18.5 2789 ϩ 5G Ͼ A c.2657 ϩ 5G Ͼ A 860 0 3120 ϩ 1G Ͼ A c.2988 ϩ 1G Ͼ A 4347 0 R1162X c.3484C Ͼ T 12,039 0 3659delC c.3528delC 7169 0 3849 ϩ 10kbC Ͼ T c.3717 ϩ 12191C Ͼ T 11,588 0 W1282X c.3846G Ͼ A 6187 0 N1303K c.3909C Ͼ G 4479 0 a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
66 For this data set, the PGM 314 chip output was 18.6 Mbp, with b03;67% aligning to the CFTR T A B L E 3 PGM CFTR Variant Coverage and Mutant Read Percentage from a Pooled Mutant Library Representing All 23 ACMG/ACOG Mutations Variant cDNA position Coverage Mutant read % Predicted read % Genotype G85E c.254G b0e; A 93 33 50 Het R117H c.350G b0e; A 6228 39 50 Het 621 af9; 1G b0e; T c.489 af9; 1G b0e; T 1243 46 50 Het 711 af9; 1G b0e; T c.579 af9; 1G b0e; T 1352 29 50 Het R334W c.1000C b0e; T 13,284 8 25 Het R347P c.1040G b0e; C 9454 27 25 Het A455E c.1364C b0e; A 19,527 43 50 Het èc;I507 c.1519_1521delATC 15,587 14 25 Het èc;F508 c.1521_1523delCTT 15,587 68 50 Homo 1717-1G b0e; A c.1585-1G b0e; A 3584 36 50 Het G542X c.1624G b0e; T 610 41 50 Het G551D c.1652G b0e; A 6714 16 17 Het R553X c.1657C b0e; T 6670 15 17 Het R560T c.1679G b0e; C 6395 22 17 Het 1898 af9; 1G b0e; A c.1766 af9; 1G b0e; A 3293 49 50 Het 2184delAa c.2052delA 2256 63 50 Het 2789 af9; 5G b0e; A c.2657 af9; 5G b0e; A 1765 54 50 Het 3120 af9; 1G b0e; A c.2988 af9; 1G b0e; A 7447 40 50 Het R1162X c.3484C b0e; T 19,060 54 50 Het 3659delC c.3528delC 28,321 30 50 Het 3849 af9; 10kbC b0e; T c.3717 af9; 12191C b0e; T 27,102 46 50 Het W1282X c.3846G b0e; A 9219 48 50 Het N1303K c.3909C b0e; G 4842 49 50 Het a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
85 Using samples characterized previously, we analyzed the PGM`s data out- T A B L E 4 PGM CFTR Variant Coverage and Mutant Read Percentage from an Individual Harboring Two Disease-Causing CFTR Mutations Variant cDNA position Coverage Mutant read % G85E c.254G b0e; A 237 0 R117H c.350G b0e; A 3774 0 621 af9; 1G b0e; T c.489 af9; 1G b0e; T 936 0 711 af9; 1G b0e; T c.579 af9; 1G b0e; T 2018 0 R334W c.1000C b0e; T 10,899 0 R347P c.1040G b0e; C 7720 0 A455E c.1364C b0e; A 14,525 0 èc;I507 c.1519_1521delATC 8855 0 èc;F508 c.1521_1523delCTT 8855 47 1717-1G b0e; A c.1585-1G b0e; A 2216 0 G542X c.1624G b0e; T 2035 41 G551D c.1652G b0e; A 4581 0 R553X c.1657C b0e; T 4545 0 R560T c.1679G b0e; C 4774 0 1898 af9; 1G b0e; A c.1766 af9; 1G b0e; A 2702 0 2184delAa c.2052delA 2837 18.5 2789 af9; 5G b0e; A c.2657 af9; 5G b0e; A 860 0 3120 af9; 1G b0e; A c.2988 af9; 1G b0e; A 4347 0 R1162X c.3484C b0e; T 12,039 0 3659delC c.3528delC 7169 0 3849 af9; 10kbC b0e; T c.3717 af9; 12191C b0e; T 11,588 0 W1282X c.3846G b0e; A 6187 0 N1303K c.3909C b0e; G 4479 0 a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment

PMID: 22271776 [PubMed] Vernooij-van Langen AM et al: "Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study."

No. Sentence Comment

80 One infant was missed because of a low PAP concentration (0.8 mg/litre); this infant had two mutations (F508del and A455E) and a positive sweat test (chloride 65 mmol/litre). Login to comment
110 Table 2 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests in infants with cystic fibrosis detected by newborn screening IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 438 5.3 F508del F508del 74 2 284 1.8 F508del F508del 88 3 266 9.8 F508del F508del 97 4 237 1.8 F508del F508del 11 and 74 5 197 4.3 F508del F508del 69 6* 191 12.6 F508del C.3889dupT 94 7 164 14.4 F508del G542X 102 8 129 4.3 F508del F508del Failed 9 110 2.2 F508del F508del 94 10 109 2.0 F508del F508del 51 11 105 4.4 F508del F508del 149 12 155 2.6 F508del F508del 111 13 191 12.6 F508del F508del 4 14 116 15.8 F508del F508del Failed 3 times 15 293 5.7 F508del 2184A 120 16* 228 15.8 F508del 1294_1300del 99 17 218 4.5 F508del G85E 99 18 153 4.0 F508del S1251N 77 19* 141 15.8 F508del E730X 82 20z 78 0.8 F508del A455E 65 21y 114 11.2 F508del F508del Failed 22y 109 0.8 F508del F508del 78 23y 93 1.3 F508del F508del e 24y 75 6.7 F508del F508del 78 *Second mutation detected by sequencing. Login to comment
79 One infant was missed because of a low PAP concentration (0.8 mg/litre); this infant had two mutations (F508del and A455E) and a positive sweat test (chloride 65 mmol/litre). Login to comment
109 Table 2 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests in infants with cystic fibrosis detected by newborn screening IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 438 5.3 F508del F508del 74 2 284 1.8 F508del F508del 88 3 266 9.8 F508del F508del 97 4 237 1.8 F508del F508del 11 and 74 5 197 4.3 F508del F508del 69 6* 191 12.6 F508del C.3889dupT 94 7 164 14.4 F508del G542X 102 8 129 4.3 F508del F508del Failed 9 110 2.2 F508del F508del 94 10 109 2.0 F508del F508del 51 11 105 4.4 F508del F508del 149 12 155 2.6 F508del F508del 111 13 191 12.6 F508del F508del 4 14 116 15.8 F508del F508del Failed 3 times 15 293 5.7 F508del 2184A 120 16* 228 15.8 F508del 1294_1300del 99 17 218 4.5 F508del G85E 99 18 153 4.0 F508del S1251N 77 19* 141 15.8 F508del E730X 82 20z 78 0.8 F508del A455E 65 21y 114 11.2 F508del F508del Failed 22y 109 0.8 F508del F508del 78 23y 93 1.3 F508del F508del e 24y 75 6.7 F508del F508del 78 *Second mutation detected by sequencing. Login to comment

PMID: 22427236 [PubMed] Rosendahl J et al: "CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?"

No. Sentence Comment

72 The following CFTR variants were analysed with specific FRET probes: p.E60X, p.R75Q, p.G85E, p.R117H, p.I148T, c.621 +1G>T (IVS4+1G>T), c.711+1G>T (IVS5+1G>T), c.1078delT, p.R334W, p.R347P, 9-13TG, 5-9T, p.A455E, p.M470V, p.F508del, c.1716G>A (p.E528E), c.1717-1G>A (IVS10-1G>A), p.G542X, p.S549N, p.R553X, p.R560T, c.1898+1G>A (IVS12 +1G>A), c.2143delT, c.2183AA>G, c.2562T>G, c.2657+5G>A (IVS14B+5G>A), p.L997F, p.I1005R, p.Y1092X, p.D1152H, p.R1162X, c.3659delC, p.S1235R, p.S1251N, p.W1282X, p.N1303K, and c.4389G>A. Login to comment
140 Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p¼0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment
69 The following CFTR variants were analysed with specific FRET probes: p.E60X, p.R75Q, p.G85E, p.R117H, p.I148T, c.621 +1G>T (IVS4+1G>T), c.711+1G>T (IVS5+1G>T), c.1078delT, p.R334W, p.R347P, 9-13TG, 5-9T, p.A455E, p.M470V, p.F508del, c.1716G>A (p.E528E), c.1717-1G>A (IVS10-1G>A), p.G542X, p.S549N, p.R553X, p.R560T, c.1898+1G>A (IVS12 +1G>A), c.2143delT, c.2183AA>G, c.2562T>G, c.2657+5G>A (IVS14B+5G>A), p.L997F, p.I1005R, p.Y1092X, p.D1152H, p.R1162X, c.3659delC, p.S1235R, p.S1251N, p.W1282X, p.N1303K, and c.4389G>A. Login to comment
135 Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p&#bc;0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment

PMID: 22423042 [PubMed] Gonska T et al: "Role of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in patients with chronic sinopulmonary disease."

No. Sentence Comment

66 All P values are two-sided with a Table 2-CFTR Genotypes Identified in Subjects With Idiopathic Sinopulmonary Disease CF Causing/CF Causing CF Causing/CFTR Mutation CFTR Mutation/CFTR Mutation CF Causing/Unknown CFTR Mutation/Unknown F508del/A455E 3x F508del /D1152H 2x D579G/D579G 2x F508del /26x R764X/2 F508del/S1251N R75X/V456A 758delC/2 F508del/L967S 1716G.A/5T 1716G.A/2 F508del/5T R75Q/5T R117H (7T)/23x F508del/3212T.C 5T/23x G542X/D1152H 1717-1G.A/Q1291H Patients are grouped according to the identified CFTR alterations on allele 1/allele 2. Login to comment

PMID: 22137130 [PubMed] Cordovado SK et al: "CFTR mutation analysis and haplotype associations in CF patients."

No. Sentence Comment

104 Mutation N alleles c.966T>G(5'flanking) c.234T>A(5'flanking)a c.-8G>C(5'UTR) c.-4G>C(Exon1) c.274-179G>A(Intron3) c.743+40A>G(Intron6) c.744-31TTGA(5_7)(Intron6) c.869+11C>T(Intron7) c.869+88T>A(Intron7) c.1209+43T>G(Intron9) IVS8CA(15-23)(Intron9) TG(10-13)_T(5-9)(Intron9) c.1393-61A>G(Intron10) M470V(Exon11) F508del(Exon11) c.1766+152T>A(Intron13) c.1767-231T>C(Intron13) c.1767-136T>C(Intron13) c.1767-132A>G(Intron13) c.2562T>G(Exon15) c.2604A>G(Exon15) c.2619+86_2619+87del(Intron15) c.2619+106T>A(Intron15) c.2909-92G>A(Intron17) IVS17bCA(11-17)(Intron20) c.3368-140A>C(Intron20) c.3469-65C>A(Intron21) F508del 32 TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- GA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- A5- 55- 55- 55- 66- 66- 66- 66- 66- 66- 66- 66- 66- 66- 55- 55- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TC- TT- TT- TT- TC- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TG- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- T17- 10_9- G- F508del- TA- 13C F508del 29 G23- 10_9- G- F508del- TA- 13C F508del 1 G21- 10_9- G- GG- G-F508del- TA- 13C F508del 1 G17- 10_9- G- F508del- A- G- delTA- 17- C- A N1303K 6 G542X 6 3849+10kbC→T 1 del Ex17a, b, Ex18 1 GG- GG- GG- 23- 10_9- GG-F508- T- TA- 13- C A455E 1 G22- 10_9- G- F508- T- TA- 13- C 621+1G→T 5 G21- 10_9- G- GG- GG- F508C- TA- 13- C 711+1G→T 3 3272-26A→G 2 3659delC 2 R347P 2 G16- 11_7- A- A-F508- TA- 13C del Ex 2, 3 2 del Ex 17a,17b 2 Normal 1 R334W 2 G17- 11_7- A- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA-AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- A-AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- F508- TA- 13C 2183AA→G 2 G16- 10_7- F508- TATA- TATA- TATA- TATA- TATA- TATA- 13C del Ex 2 1 G16- 11_7- F508- 14C 1288insTA 1 G16- 12_7- F508- 13C Normal 1 G16- 12_7- F508- 13C R1162X 1 G17- 10_7- F508- 13C del Ex 2,3 1 G16- 11_7- F508- A17- C del Ex 17a,17b 1 GA- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT-16- 11_7- F508- 14- C G85E 1 G16- 11_7- F508- 15C 1898+1G→A 1 G16- 11_7- F508- G13- C no mut detected 1 GT- TT- T16- 10_7- F508- 13C no mut detected 1 G16- 10_7- F508- 17A W1282X 2 G17- 10_7- F508- 17A W1282X 4 GC- CC- C17- 10_7- F508- delTA- 17- A Q39X 1 I507del 1 3849+10kbC→T 1 R560T 2 1717-1G→A 2 G551D 3 G16- 10_7- F508- delTA- 17- A G551D 2 1154insTC 1 G16- 10_7- F508- delTA- 17- 1717- 17A 1717-1G→A 1 2789+5G→A 1 GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- G17- 10_7- F508- AdelTA- A R1066C 1 GG- 17- 10_7- F508- delTA- A R1066H 1 GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- G17- 9_7- F508- delTAC R553X 3 GG- GG- CA- AA- AA- AA- A17- 12_7- F508- delTA- 11- C 3121-1G→A 1 C17- 12_7- F508- delTA- 11- C R334W 1 G17- 12_7- F508- TA- 13- C (TG)13T5b 1 G17- 13_5- F508- delTA- 13- C CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- R117H 1 CA- 6C- TT- 15- 12_5- AG- F508- T- TT- AT- ATA- TG- 13A- C R117H1 1 CA- 6C- TT- 16- 12_5- AG- F508- T- TT- AT- ATA- TG- 13A- C 1717-1G→A 1 R117Hb 1 GA- 6C- TT- 16- 10_7- AA- F508- A- TC- AG- AdelTA- TG- 13A- C 144c a Variation found in a sample where the haplotype could not be predicted. Login to comment

PMID: 22256939 [PubMed] Massie RJ et al: "Lessons learned from 20 years of newborn screening for cystic fibrosis."

No. Sentence Comment

30 Where possible, all patients with a diagnosis of CF had further CFTR mutation analysis performed in an attempt to clarify the genotype (p.A455E, p.S549N, p.R347H, p.R1162X, p.R347P, p.R334W, p.R117H). Login to comment

PMID: 21843195 [PubMed] Nathan AM et al: "First study of the F508del mutation in Malaysian children diagnosed with cystic fibrosis."

No. Sentence Comment

48 Letters to the Editor Journal of Paediatrics and Child Health 47 (2011) 572-575 (c) 2011 The Authors Journal of Paediatrics and Child Health (c) 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians) Table1Summaryoftheclinicalcharacteristics,sweattestresultsandcysticfibrosistransmembraneconductanceregulatormutationstudiesofthepatientsdiagnosedwithcysticfibrosisinUniversity MalayaMedicalCenterfrom2000to2009 PatientAgeat presentation PresentingsymptomsOtherfindingsConsanguinityRaceSweatconductivity (mmol/l) KS score Mutations Rin3monthsRecurrentpneumoniaandFTTPseudo-Bartter`ssyndromeYesIndian13440†Nonedetected Nes8yearsSeverepersistentasthmaFTTNoIndian12450F508del/unknown Abd4monthsSeverepneumoniaandventilator dependent FTTYesYemeni11730F508del/F508del Ben7yearsCirrhosisoftheliverwithportal hypertension FTTUnknown(adopted)Unknown14080†Nonedetected(7T polymorphism) Sak3monthsRecurrentpneumoniaandFTTNDYesIndian11350F508del/F508del Ngan3yearsPseudo-Bartter`ssyndromeNDNoChinese13790Notdone(parentsrefused) LJH5monthsPseudo-Bartter`ssyndromeRecurrentpneumoniaNoChinese/Indonesian9465F508delnegative Josh5monthsPseudo-Bartter`ssyndromeandFTTNDNoIndian8585†Nonedetected Nur3monthsChronicdiarrhoeaandFTTPseudo-Bartter`ssyndromeNoMalay/Chinese13085‡†R553X/nonedetected Vin4monthsRecurrentpneumoniaandFTTNDNoChinese12260F508delnegative Muh5yearsPoorlycontrolledasthmaNDNoMalay10765F508delnegative Naz3monthsFTTandsteatorrhoeaRecurrentlunginfectionsand pseudo-Bartter`s NoMalay14675F508delnegative Additionalmutationsscreenedinthefourpatients:†F508del,I506/7del,G551D,G542X,R553X,R117C,R117H,621+1G>T,V520F,A455E,N1303K,3849+10kbC>T.‡R334W,R347P,A455E,S549N,R560T, 3659delC,W1282X.FTT,failuretothrive;KS,Schwachman-Kulczycki(KS)score;ND,nodata. Login to comment

PMID: 22439061 [PubMed] Mesoraca A et al: "The use of DHPLC (Denaturing High Performance Liquid Chromatography) in II level screening of the CFTR gene in Prenatal Diagnosis."

No. Sentence Comment

100 48 Journal of Prenatal Medicine 2010; 4 (3): 45-50 Table III Mutations found with II level screening through DHPLC Mutations of mutated alleles DF508 29 W1282X 3 N1303K 8 1717-1G®A 2 3659delC 1 G85E 1 2789 +5G®A 2 R553X 2 R1162X 1 R117H 1 G542X 3 Total 53Table I Mutations found through I level screeningMutations analysed with I level screening through OLA CFTR Mutations Position on the CFTR gene DF508 Exon 10 3849+10KbC®T Intron 19 R334W Exon 7 W1282X Exon 10 V520F Exon 10 3905insT Exon 20 N1303K Exon 21 3876delA Exon 20 1717-1G®A Exon 11 3659delC Exon 19 DI507 Exon 10 A455E Exon 9 G85E Exon 3 2789 +5G®A Exon 14 / Intron 14 2183AA®G Exon 13 1898+1G®A Exon 12 / Intron 12 R347P Exon 7 R347H Exon 7 R560T Exon 11 1078delT Exon 7 R553X Exon 11 711+1G®T Exon 5 / Intron 5 G551D Exon 11 R1162X Exon 19 S549R Exon 11 R117H Exon 4 S549N Exon 11 621+1G®T Exon 4 G542X Exon 11 394delTT Exon 3 3120+1G®ðA Exon 16/ Intron 16 2184delA Exon 13 Table II Mutations found through I level screening Mutations Positions on CFTR gene R1066C Exon 17 b L1065P Exon 17 b A1006E Exon 19 R75Q Exon 3 D537E Exon 11 W1134X Exon 18 W1145X Exon 18 L1077P Exon 17b C524X Exon 11 Total 9 The use of DHPLC (Denaturing High Performance Liquid Chromatography) in II level screening of the CFTR gene in Prenatal Diagnosis Journal of Prenatal Medicine 2010; 4 (3): 45-50 49 tion was to provide the couple with adequate counselling in order to better understand the genotype-phenotype correlation in the various associations of mutations. Login to comment

PMID: 19615439 [PubMed] Davidson H et al: "An immunocytochemical assay to detect human CFTR expression following gene transfer."

No. Sentence Comment

215 CF genotypes for nasal brushings were 15 DF508/DF508, 2 DF508/ND, 1 DF508/A455E, 1 DF508/G551D, 1 G85E/ND, 1 ND/ND (where 'ND` indicates that none of the 31 most common mutations was detected). Login to comment
218 CF genotypes for nasal brushings were 15 DF508/DF508, 2 DF508/ND, 1 DF508/A455E, 1 DF508/G551D, 1 G85E/ND, 1 ND/ND (where 'ND` indicates that none of the 31 most common mutations was detected). Login to comment

PMID: 18992954 [PubMed] Henckaerts L et al: "Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis."

No. Sentence Comment

91 There was Table 4 Summary of the 37 CFTR variants studied in the exploratory phase INNO-LiPA CFTR 19 INNO-LiPA CFTR17+Tn Update F508del 621+1GfiT G542X 3849+10kbCfiT N1303K 2183AAfiG W1282X 394delTT G551D 2789+5GfiA 1717-1GfiA R1162X R553X 3659delC CFTRdele2,3(21kb) R117H I507del R334W 711+1GfiT R347P 3272-26AfiG G85E 3905insT 1078delT R560T A455E 1898+1GfiA 2143delT S1251N E60X I148T 2184delA 3199del6 711+5GfiA 3120+1GfiA Tn Q552X Fig. 1. Login to comment

PMID: 18243066 [PubMed] Ratbi I et al: "Cystic fibrosis carrier frequency and estimated prevalence of the disease in Morocco."

No. Sentence Comment

27 We screened for 32 CFTR gene mutations (G85E, 394delTT, R117H, 621+1GNT, 711+1GNT, R334W, R347P, R347H, 1078delT, A455E, I507del, F508del, V520F, 1717-1GNA, G542X, G551D, R553X, R560T, S549R(TNG), S549N, 1898+1GNA, 2183AANG, 2184delA, 2789+5GNA, 3120 + 1G NA, R1162X, 3659delC, 3849 + 10kbC NT, W1282X, 3905insT, 3876delA, N1303K) and the (T)5 splicing variant of intron 8, using a commercial kit (CF v3 Genotyping Assay, Abbott, Rungis, France). Login to comment

PMID: 18687795 [PubMed] Audrezet MP et al: "Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

51 Sequences of the Primers Used for CFTR Analysis by HRM, GC Size, Amplicon Length, Number of Positive Controls Validated for Each Exon, and Positive Controls for Routine Analysis Exon Primer Sequences GC length Amplicon length (bp) Introns Number of heterozygous- positive controls Number of homozygous- positive controls Recommended control 1 LSCFE1Fmod 5Ј-CCGCCGCCGTTGAGCGGCAGGCACC-3Ј 8 200 bp 74 4 125GϾC LSCFE1Rmod 5Ј-CCGCCGCCGGCACGTGTCTTT CCGAAGCT-3Ј 8 19 M1I 2 2i5b 5Ј-CAAATCTGTATGGAGACC-3Ј 0 194 bp 39 5 R31C 2i3Љ 5Ј-CAACTAAACAATGTACATGAAC-3Ј 0 4 296ϩ1GϾT 3 LSCFe3Fmod LSCFe3Rmod 5Ј-CGCCGTTAAGGGAAATAGGACAA CTAAAATA-3Ј 5 276 bp 44 10 2 R75Q 5Ј-CCGCCGATTCACCAGATTTCGTAGTC-3Ј 6 66 G85V 4 LSCFe4FmodC 5Ј-CCGCCGCCGCCCGTGTTGAAATT CTCAGGGT-3Ј 12 361 bp 52 14 1 R117H LSCFe4RmodC 5Ј-CCGCCGCCCACATGTACGATAC AGAATATATGTGCC-3Ј 9 26 574delA 5 LSCFE5Fmod 5Ј-CCGCCGGTTGAAATTATCTAACTTTCC-3Ј 6 201 bp 13 8 624delT LSCFE5Rmod 5Ј-CCGAACTCCGCCTTTCCAGTTGT-3Ј 3 48 711ϩ1GϾT 6a LSCF6aFmod2 5Ј-CCGCCGGGGTGGAAGAT ACAATGACACCTG-3Ј 5 317 bp 25 8 C225X LSCF6aRmod2 5Ј-CCGCCGCCGCGATGCATAGAG CAGTCCTGGTT-3Ј 11 66 L206W 6b LSCFE6bFmod 5Ј-CGCGCCGCCGGATTTAC AGAGATCAGAGAG-3Ј 10 239 bp 0 2 1 R258G LSCFE6Brmod 5Ј-CCGCCGCCGAGGTGGA GTCTACCATGA-3Ј 8 66 1001ϩ11CϾT 7 LSCFE7Fmod2 5Ј-CCGCCGCCCTCTCCCTGAATTT TATTGTTATTGTTT-3Ј 13 326 bp 7 11 1078delT LSCFE7Rmod2 5Ј-CCCGCCGCCCTATAATGCAG CATTATGGT-3Ј 10 7 1248ϩ1GϾT 8 LSCFE8Fmod 5Ј-CCGGAATGCATTAATGCTAT TCTGATTC-3Ј 4 199 bp 32 7 W401X LSCFE8Rmod 5Ј-CCCGCAGTTAGGTGTTTAG AGCAAACAA-3Ј 4 18 1249-5AϾG 9 LSCFe9Fmod2 5Ј-CCGCCGCCGGGAATTATTTGAGAA AGCAAAACA-3Ј 8 279 bp 0 3 D443Y LSCFe9Rmod2 5Ј-CCGCCGCGAAAATACCTTCCAG CACTACAAACTAGAAA-3Ј 8 57 A455E 10 LSCF10FmodD 5Ј-CGCCGTTATGGGAGAACTGG AGCCTTCAGAG-3Ј 5 275 bp 0 15 1 F508del LSCF10RmodD 5Ј-CCGCAGACTAACCGATTGAAT ATGGAGCC-3Ј 4 68 E528E 11 h11i5 5Ј-TGCCTTTCAAATTCAGATTGAGC-3Ј 0 197 bp 42 13 2 G542X 11i3ter 5Ј-ACAGCAAATGCTTGCTAGACC-3Ј 0 17 G551D 12 LSCFE12Fmod 5Ј-CGCGTCATCTACACTAGATGACCAG-3Ј 4 244 bp 43 15 G576A 1898 ϩ 1GϾALSCFE12Rmod 5Ј-CCGGAGGTAAAATGCAATCTATGATG-3Ј 3 63 13 LSCF13AFmod 5Ј-CCGCCGCCGGAGACATATTG CAATAAAGTAT-3Ј 9 38 20 I601F LSCF13ARmod 5Ј-GCCTGTCCAGGAGACAGGA GCATCTC-3Ј 2 R668C LSCF13BFmod 5Ј-CCGCCGCAATCCTAACTGAG ACCTTACACCG-3Ј 2 R668C LSCF13BRmod 5Ј-CCGCCGATCAGGTTCAGGA CAGACTGC-3Ј 3 346 bp 2184insA LSCF13CFmod 5Ј-CCGCGGTGATCAGCACTGGCCC-3Ј 6 301 bp 77 L749L LSCF13CRmod 5Ј-CCGCGCGCGCGGCCAGTTTCTTG AGATAACCTTCT-3Ј 13 259 bp V754M LSCF13DFmod 5Ј-CGTGTCACTGGCCCCTCAGGC-3Ј 1 221 bp I807M LSCF13DRmof 5Ј-CCGCCGCCGCTAATCCTATGA TTTTAGTAAAT-3Ј 9 220 bp 2622ϩ1GϾA LSCf13FFmod 5Ј-CGCGGTGCAGAAAGAAGAAAT TCAATCCTAACTG-3Ј 4 R668C LSCF13FRmod 5Ј-CCGCCGTGCCATTCATTTGT AAGGGAGTCT-3Ј 6 2184insA 14a LSCF14aFmodB 5Ј-CCGACCACAATGGTGGCAT GAAACTG-3Ј 3 239 bp 35 7 1 T854T LSCF14aRmodB 5Ј-CCGCCGACTTTAAATCCAGTAAT ACTTTACAATAGAACA-3Ј 6 7 W846X 14b LSCF14bFmod 5Ј-CCGGAGGAATAGGTGAAGAT-3Ј 2 179 bp 38 4 2752-5GϾT LSCF14bRmodb 5Ј-CCGTACATACAAACATAGTGGATT-3Ј 3 59 2789ϩ5GϾT 15 LSCFE15Fmod 5Ј-CGCGCCGTGTATTGGAAA TTCAGTAAGTAACTTTGG-3Ј 7 412 bp 33 16 T908S LSCFE15Rmod 5Ј-CCGCAGCCAGCACTGCCAT TAGAAA-3Ј 4 68 S945L (table continues) phisms that we have chosen to exclude. Login to comment

PMID: 18456578 [PubMed] Castellani C et al: "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice."

No. Sentence Comment

1236 Table 1 Geographical distribution of the most common mutations E60X Southern European S549N Indian CFTR Slavic - Eastern European G551D United Kingdom, Central Europe R75X Southern European, US-Hispanic Q552X Southern European, Italian 394delTT Nordic - Baltic sea region R553X Central European G85E Southern Europe A559T African-American 406-1GNA US-Hispanic R560T Northern Irish R117H European-derived populations 1811+1.6kbANG Spanish, US-Hispanic R117C Northern European 1898+1GNA United Kingdom, Central Europe 621+1GNT Southern European 1898+5GNT East Asian populations 711+1GNT French, French Canadian 2143delT Slavic - Eastern European 711+5GNA US-Hispanic 2183delAANG Southern Europe, Middle Eastern, Iranian, Latin American L206W Spanish and US-Hispanic 2184delA European-derived populations V232D Spanish and US-Hispanic 2789+5GNA European-derived populations 1078delT French Brittany Q890X Southern European R334W Southern European, Latin American 3120+1GNA African, Arabian, African-American, Southern Europe 1161delC Indian 3272-26ANG European-derived populations R347P European-derived, Latin America 3659delC Scandinavian R347H Turkish 3849+10kbCNT Ashkenazi-Jewish, Southern European, Middle Eastern, Iranian, Indian A455E Dutch R1066C Southern European 1609delCA Spanish, US-Hispanic Y1092X (CNA) Southern European I506T Southern European, Spanish M1101K US-Hutterite I507del European-derived populations 3905insT Swiss F508del European-derived populations D1152H European-derived populations 1677delTA Southern European, Middle Eastern R1158X Southern European 1717-GNA European-derived populations R1162X Italian, Amerindian, Latin America V520F Irish S1251N European-derived populations G542X Southern European, Mediterranean W1282X Ashkenazi-Jewish, Middle Eastern S549R(TNG) Middle Eastern N1303K Southern European, Middle Eastern Legend: these alleles occur with a frequency superior to 0.1% in selected populations. Login to comment
1239 Table 1 Geographical distribution of the most common mutations E60X Southern European S549N Indian CFTR Slavic - Eastern European G551D United Kingdom, Central Europe R75X Southern European, US-Hispanic Q552X Southern European, Italian 394delTT Nordic - Baltic sea region R553X Central European G85E Southern Europe A559T African-American 406-1GNA US-Hispanic R560T Northern Irish R117H European-derived populations 1811+1.6kbANG Spanish, US-Hispanic R117C Northern European 1898+1GNA United Kingdom, Central Europe 621+1GNT Southern European 1898+5GNT East Asian populations 711+1GNT French, French Canadian 2143delT Slavic - Eastern European 711+5GNA US-Hispanic 2183delAANG Southern Europe, Middle Eastern, Iranian, Latin American L206W Spanish and US-Hispanic 2184delA European-derived populations V232D Spanish and US-Hispanic 2789+5GNA European-derived populations 1078delT French Brittany Q890X Southern European R334W Southern European, Latin American 3120+1GNA African, Arabian, African-American, Southern Europe 1161delC Indian 3272-26ANG European-derived populations R347P European-derived, Latin America 3659delC Scandinavian R347H Turkish 3849+10kbCNT Ashkenazi-Jewish, Southern European, Middle Eastern, Iranian, Indian A455E Dutch R1066C Southern European 1609delCA Spanish, US-Hispanic Y1092X (CNA) Southern European I506T Southern European, Spanish M1101K US-Hutterite I507del European-derived populations 3905insT Swiss F508del European-derived populations D1152H European-derived populations 1677delTA Southern European, Middle Eastern R1158X Southern European 1717-GNA European-derived populations R1162X Italian, Amerindian, Latin America V520F Irish S1251N European-derived populations G542X Southern European, Mediterranean W1282X Ashkenazi-Jewish, Middle Eastern S549R(TNG) Middle Eastern N1303K Southern European, Middle Eastern Legend: these alleles occur with a frequency superior to 0.1% in selected populations. Login to comment

PMID: 17481968 [PubMed] Storm K et al: "High incidence of the CFTR mutations 3272-26A-->G and L927P in Belgian cystic fibrosis patients, and identification of three new CFTR mutations (186-2A-->G, E588V, and 1671insTATCA)."

No. Sentence Comment

32 The Inno Lipa™ CFTR17 assay contains normal and mutant probes for 17 other CFTR mutations (394delTT, G85E, 621+1G→T, R117H, 1078delT, R347P, R334W, E60X, 711+5G→A, 2789 + 5G→ A, R1162X, 3659delC, 3849 + 10kbC→ T, 2143delT, A455E, 2183AA→G, 2184delA) (Innogenetics). Login to comment

PMID: 16423550 [PubMed] Ramirez AM et al: "Mutational spectrum of cystic fibrosis patients from Cordoba province and its zone of influence: implications of molecular diagnosis in Argentina."

No. Sentence Comment

44 Mutations (p.F508del, p.N1303K, p.G542X, p.R334W, c.2789 + 5G > A, c.3659delC, p.R553X, c.3849 + 10kbC > T, p.R1162X, c.621 + 1G > T, p.W1282X, p.R117H, c.1078delT, p.E60X, p.R347P, p.A455E, p.I507del, c.1717-1G > A, p.G551D, [c.2183A > G; c.2184delA] and p.S1251N) were analyzed by heteroduplex analysis on polyacrylamide gel electrophoresis [11,12] and by ampliWcation refractory mutation system [13] in all 78 patients. Login to comment

PMID: 16458894 [PubMed] Ayala YM et al: "TDP43 depletion rescues aberrant CFTR exon 9 skipping."

No. Sentence Comment

13 Among these are mutations in composite exonic regulatory elements of splicing (CERES) that disrupt positive regulatory elements and thus result in exon skipping (e.g., A455E) [5]. Login to comment
95 One of the positive elements, found in the exon, can be affected by a naturally occurring mutation associated with CF (A455E). Login to comment
147 Therefore, TDP43 downregulation would also improve CFTR expression in cases of positive splicing element disruption, such as in the A455E (C1496A) mutation. Login to comment
94 One of the positive elements, found in the exon, can be affected by a naturally occurring mutation associated with CF (A455E). Login to comment
146 Therefore, TDP43 downregulation would also improve CFTR expression in cases of positive splicing element disruption, such as in the A455E (C1496A) mutation. Login to comment

PMID: 16157443 [PubMed] Stipoljev F et al: "Cytogenetic analysis of azoospermic patients: karyotype comparison of peripheral blood lymphocytes and testicular tissue."

No. Sentence Comment

64 T; intron 8/exon 9: A455E, 5T/7T/9T and LightCycler-based fluorescent-labeled oligonucleotide melting assays (DF508) [5]. Login to comment

PMID: 16798543 [PubMed] Davies JC et al: "New tests for cystic fibrosis."

No. Sentence Comment

46 A very small number of mutations which appear to confer a mild pulmonary phenotype have been described, such as A455E and R117H. Login to comment

PMID: 16051530 [PubMed] Kinnunen S et al: "Spectrum of mutations in CFTR in Finland: 18 years follow-up study and identification of two novel mutations."

No. Sentence Comment

36 The InnoLipa assay recognizes 36 mutations: E60X (c.178G>T, p.Glu60X), G85E (c.254G>A, p.Gly85- Glu), 394delTT, R117H (c.350G>A, p.Arg117His), I148T (c.443T>C, p.Ile148Thr), 621+1G>T (c.489+1G>T), 711+1G>T (c.579+1G>T), 711+5G>A (c.579+5G>A), 1078delT (c.948delT, p.Phe316fs), R334W (c.1000C>T, p.Arg334Trp), R347P (c.1040G>C, p.Arg347Pro), A455E (c.1364C>A, p.Ala455Glu), I507del (c.1519_1521delATC, p.Ile507del), F508del, 1717À1G>A (c.1585À1G>A), G542X, G551D (c.1652G >A, p.Gly551Asp), Q552X (c.1654C > T, p.Gln552X), R553X (c.1657C > T, p.Arg553X), R560T (1679G>vC, p.Arg560Thr), 1898+ 1G > A (c.1766 + 1G > A), 2143delT (c.2012delT, p.Leu671fs), 2183AA > G (c.2051_2052delAAinsG, p.Lys684fs), 2184delA (c.2052delA, p.Lys684fs), 2789+ 5G>A (c.2657+5G>A), 3120+1G>A (c.2988+1G>A), 3199del6 (c.3067_3072del, p.Ile1023_Val1024del), 3272À 26A > G (c.3140 À26A > G), R1162X (c.3484C > T, p.Arg1162X), 3849+10kbCYT, 3659delC (c.3528delC, p.Lys1177fs), S1251N (c.3752G > A, p.Ser1251Asn), 3905insT (c.3773dupT, p.Leu1258fs), W1282X (c.3846G> A, p.Trp1282X), N1303K (c.3909C>G, p.Asn1303Lys), CFTRdele2,3(21kb) and Tn-polymorphism on intron 8. Login to comment
37 The InnoLipa assay recognizes 36 mutations: E60X (c.178G>T, p.Glu60X), G85E (c.254G>A, p.Gly85Glu), 394delTT, R117H (c.350G>A, p.Arg117His), I148T (c.443T>C, p.Ile148Thr), 621+1G>T (c.489+1G>T), 711+1G>T (c.579+1G>T), 711+5G>A (c.579+5G>A), 1078delT (c.948delT, p.Phe316fs), R334W (c.1000C>T, p.Arg334Trp), R347P (c.1040G>C, p.Arg347Pro), A455E (c.1364C>A, p.Ala455Glu), I507del (c.1519_1521delATC, p.Ile507del), F508del, 1717 1G>A (c.1585 1G>A), G542X, G551D (c.1652G >A, p.Gly551Asp), Q552X (c.1654C > T, p.Gln552X), R553X (c.1657C > T, p.Arg553X), R560T (1679G>vC, p.Arg560Thr), 1898+ 1G > A (c.1766 + 1G > A), 2143delT (c.2012delT, p.Leu671fs), 2183AA > G (c.2051_2052delAAinsG, p.Lys684fs), 2184delA (c.2052delA, p.Lys684fs), 2789+ 5G>A (c.2657+5G>A), 3120+1G>A (c.2988+1G>A), 3199del6 (c.3067_3072del, p.Ile1023_Val1024del), 3272 26A > G (c.3140 26A > G), R1162X (c.3484C > T, p.Arg1162X), 3849+10kbCYT, 3659delC (c.3528delC, p.Lys1177fs), S1251N (c.3752G > A, p.Ser1251Asn), 3905insT (c.3773dupT, p.Leu1258fs), W1282X (c.3846G> A, p.Trp1282X), N1303K (c.3909C>G, p.Asn1303Lys), CFTRdele2,3(21kb) and Tn-polymorphism on intron 8. Login to comment

PMID: 16378926 [PubMed] Marcus-Soekarman D et al: "Hyperechogenic fetal bowel: counseling difficulties."

No. Sentence Comment

67 Routine CFTR-mutation analysis, using Table 1 CFTR-mutations screened for in the first step E60X 2143delT G542X G85E 2183AA-G G551D 394delTT 2184delA Q552X 621 + 1G-T 2789 + 5G-A R553X R117H 3849 + 10kbC-T R560T 711 + 5G-A R1162X S1251N 1078delT 3659delC 390insT R334W delta I507 W1282X R347P delta F508 N1303K A455E 1717-1G-A a panel of 29 CFTR-mutations, detects only 41.6% of CFTR-mutations in the Turkish population [1]. Login to comment

PMID: 16049310 [PubMed] Schrijver I et al: "Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations."

No. Sentence Comment

51 Complete List of Mutations Detectable with the CF APEX Assay CFTR location Amino acid change Nucleotide change 1 E 1 Frameshift 175delC 2 E 2,3 Frameshift del E2, E3 3 E 2 W19C 189 GϾT 4 E 2 Q39X 247 CϾT 5 IVS 2 Possible splicing defect 296 ϩ 12 TϾC 6 E 3 Frameshift 359insT 7 E 3 Frameshift 394delTT 8 E 3 W57X (TAG) 302GϾA 9 E 3 W57X (TGA) 303GϾA 10 E 3 E60X 310GϾT 11 E 3 P67L 332CϾT 12 E 3 R74Q 353GϾA 13 E 3 R75X 355CϾT 14 E 3 G85E 386GϾA 15 E 3 G91R 403GϾA 16 IVS 3 Splicing defect 405 ϩ 1GϾA 17 IVS 3 Possible splicing defect 405 ϩ 3AϾC 18 IVS 3 Splicing defect 406 - 1GϾA 19 E 4 E92X 406GϾT 20 E 4 E92K 406GϾA 21 E 4 Q98R 425AϾG 22 E 4 Q98P 425AϾC 23 E 4 Frameshift 444delA 24 E 4 Frameshift 457TATϾG 25 E 4 R117C 481CϾT 26 E 4 R117H 482GϾA 27 E 4 R117P 482GϾC 28 E 4 R117L 482GϾT 29 E 4 Y122X 498TϾA 30 E 4 Frameshift 574delA 31 E 4 I148T 575TϾC 32 E 4 Splicing defect 621GϾA 33 IVS 4 Splicing defect 621 ϩ 1GϾT 34 IVS 4 Splicing defect 621 ϩ 3AϾG 35 E 5 Frameshift 624delT 36 E 5 Frameshift 663delT 37 E 5 G178R 664GϾA 38 E 5 Q179K 667CϾA 39 IVS 5 Splicing defect 711 ϩ 1GϾT 40 IVS 5 Splicing defect 711 ϩ 1GϾA 41 IVS 5 Splicing defect 712 - 1GϾT 42 E 6a H199Y 727CϾT 43 E 6a P205S 745CϾT 44 E 6a L206W 749TϾG 45 E 6a Q220X 790CϾT 46 E 6b Frameshift 935delA 47 E 6b Frameshift 936delTA 48 E 6b N287Y 991AϾT 49 IVS 6b Splicing defect 1002 - 3TϾG 50 E 7 ⌬F311 3-bp del between nucleotides 1059 and 1069 51 E 7 Frameshift 1078delT 52 E 7 Frameshift 1119delA 53 E 7 G330X 1120GϾT 54 E 7 R334W 1132CϾT 55 E 7 I336K 1139TϾA 56 E 7 T338I 1145CϾT 57 E 7 Frameshift 1154insTC 58 E 7 Frameshift 1161delC 59 E 7 L346P 1169TϾC 60 E 7 R347H 1172GϾA 61 E 7 R347P 1172GϾC 62 E 7 R347L 1172GϾT 63 E 7 R352Q 1187GϾA 64 E 7 Q359K/T360K 1207CϾA and 1211CϾA 65 E 7 S364P 1222TϾC 66 E 8 Frameshift 1259insA 67 E 8 W401X (TAG) 1334GϾA 68 E 8 W401X (TGA) 1335GϾA 69 IVS 8 Splicing changes 1342 - 6 poly(T) variants 5T/7T/9T 70 IVS 8 Splicing defect 1342 - 2AϾC Table 1. Continued CFTR location Amino acid change Nucleotide change 71 E 9 A455E 1496CϾA 72 E 9 Frameshift 1504delG 73 E 10 G480C 1570GϾT 74 E 10 Q493X 1609CϾT 75 E 10 Frameshift 1609delCA 76 E 10 ⌬I507 3-bp del between nucleotides 1648 and 1653 77 E 10 ⌬F508 3-bp del between nucleotides 1652 and 1655 78 E 10 Frameshift 1677delTA 79 E 10 V520F 1690GϾT 80 E 10 C524X 1704CϾA 81 IVS 10 Possible splicing defect 1717 - 8GϾA 82 IVS 10 Splicing defect 1717 - 1GϾA 83 E 11 G542X 1756GϾT 84 E 11 G551D 1784GϾA 85 E 11 Frameshift 1784delG 86 E 11 S549R (AϾC) 1777AϾC 87 E 11 S549I 1778GϾT 88 E 11 S549N 1778GϾA 89 E 11 S549R (TϾG) 1779TϾG 90 E 11 Q552X 1786CϾT 91 E 11 R553X 1789CϾT 92 E 11 R553G 1789CϾG 93 E 11 R553Q 1790GϾA 94 E 11 L558S 1805TϾC 95 E 11 A559T 1807GϾA 96 E 11 R560T 1811GϾC 97 E 11 R560K 1811GϾA 98 IVS 11 Splicing defect 1811 ϩ 1.6 kb AϾG 99 IVS 11 Splicing defect 1812 - 1GϾA 100 E 12 Y563D 1819TϾG 101 E 12 Y563N 1819TϾA 102 E 12 Frameshift 1833delT 103 E 12 D572N 1846GϾA 104 E 12 P574H 1853CϾA 105 E 12 T582R 1877CϾG 106 E 12 E585X 1885GϾT 107 IVS 12 Splicing defect 1898 ϩ 5GϾT 108 IVS 12 Splicing defect 1898 ϩ 1GϾA 109 IVS 12 Splicing defect 1898 ϩ 1GϾC 110 IVS 12 Splicing defect 1898 ϩ 1GϾT 111 E 13 Frameshift 1924del7 112 E 13 del of 28 amino acids 1949del84 113 E 13 I618T 1985TϾC 114 E 13 Frameshift 2183AAϾG 115 E 13 Frameshift 2043delG 116 E 13 Frameshift 2055del9ϾA 117 E 13 D648V 2075TϾA 118 E 13 Frameshift 2105-2117 del13insAGAA 119 E 13 Frameshift 2108delA 120 E 13 R668C 2134CϾT 121 E 13 Frameshift 2143delT 122 E 13 Frameshift 2176insC 123 E 13 Frameshift 2184delA 124 E 13 Frameshift 2184insA 125 E 13 Q685X 2185CϾT 126 E 13 R709X 2257CϾT 127 E 13 K710X 2260AϾT 128 E 13 Frameshift 2307insA 129 E 13 V754M 2392GϾA 130 E 13 R764X 2422CϾT 131 E 14a W846X 2670GϾA 132 E 14a Frameshift 2734delGinsAT 133 E 14b Frameshift 2766del8 134 IVS 14b Splicing defect 2789 ϩ 5GϾA 135 IVS 14b Splicing defect 2790 - 2AϾG 136 E 15 Q890X 2800CϾT 137 E 15 Frameshift 2869insG 138 E 15 S945L 2966CϾT 139 E 15 Frameshift 2991del32 140 E 16 Splicing defect 3120GϾA interrogation: ACCAACATGTTTTCTTTGATCTTAC 3121-2A3G,T S; 5Ј-ACCAACATGTTTTCTTTGATCTTAC A GTTGTTATTAATTGTGATTGGAGCTATAG-3Ј; CAACAA- TAATTAACACTAACCTCGA 3121-2A3G,T AS. Login to comment
73 Genomic DNA Samples Used for Mutation Evaluation on the APEX Array Mutations validated with native DNA CFTRdel 2,3 (21 kb) 394delTT G85E R75X 574delA Y122X R117C R117H 621 ϩ 1GϾT 621 ϩ 3AϾG 711 ϩ 1GϾT I336K R334W R347P IVS8-5T IVS8-7T IVS8-9T A455E ⌬F508 ⌬I507 1677delTA 1717 - 1GϾA G542X G551D R553X R560T S549N 1898 ϩ 1GϾA 1898 ϩ 1GϾC 2183AAϾG 2043delG R668C 2143delT 2184delA 2184insA 2789 ϩ 5GϾA S945L 3120 ϩ 1GϾA I1005R 3272 - 26AϾG R1066C G1069R Y1092X (CϾA) 3500 - 2AϾT R1158X R1162X 3659delC S1235R 3849 ϩ 10 kb CϾT W1282X primer. Login to comment

PMID: 15681482 [PubMed] Chou LS et al: "Complete gene scanning by temperature gradient capillary electrophoresis using the cystic fibrosis transmembrane conductance regulator gene as a model."

No. Sentence Comment

75 Mutation Samples with Known Genotypes Scanned by TGCE* Exon Mutation† Amplicon size (bp) Location of mutation from 5Ј end (bp) Base change Detection‡ 3 G85E 234 124 G to A 1/1 3 394delTT 234 132 del TT 1/1 4 R117H 270 83 G to T 2/2 4 I148T 270 176 T to C 3/3 Intron 4 621 ϩ 1 G/T 270 233 G to T 1/1 5 663delT/663delT 186 75 del T 0/1 Intron 5 711 ϩ 1 G/T 186 124 G to T 1/1 7 R334W 345 208 C to T 1/1 7 R347P 345 248 G to C 1/1 9 A455E 263 155 C to A 2/2 10 I506V 292 168 A to G 1/1 10 ⌬I507 292 171 del ATC 2/2 10 ⌬F508 292 174 del TTT 2/2 10 ⌬F508/⌬F508 292 174 del TTT 0/1 10 F508C 292 175 T to G 1/1 10 V520F 292 210 G to T 1/1 Intron 10 1717-1 G/A 175 50 G to A 1/1 11 G542X 175 90 G to T 2/2 11 G542X/G542X 175 90 G to T 0/1 11 G551D 175 118 G to A 3/3 11 R553X 175 123 C to T 3/3 11 R560T 175 145 G to C 2/2 13 2184delA 834 356 del A 1/1 Intron 14b 2789 ϩ 5G/A 192 102 G to A 1/1 Intron 16 3120 ϩ 1G/A 216 111 G to A 1/1 19 R1162X 322 68 C to T 1/1 19 3659delC 322 111 del C 1/1 20 W1282X 206 154 G to A 1/1 21 N1303K 250 175 C to G 2/2 Total exon/intron Overall accuracy 17 93% *Samples were compared with their respective wild-type control (confirmed by sequencing). Login to comment
118 Another example of reduced resolution is heterozygous A455E in exon 9. Login to comment
119 A shoulder instead of a small peak was observed in heterozygous A455E when compared to the wild-type control (Figure 5, A and B). Login to comment
149 A: Wild-type (exon 9 of the CFTR gene); B: A455E heterozygous (exon 9 of the CFTR gene). Login to comment
156 In addition, we have sequenced exon 9 for all 12 samples because the mutation A455E is difficult to be detected in some systems. Login to comment

PMID: 16156102 [PubMed] Dunbar SA et al: "Rapid screening for 31 mutations and polymorphisms in the cystic fibrosis transmembrane conductance regulator gene by Lminex xMAP suspension array."

No. Sentence Comment

25 A 635-nm 10-mW red diode laser excites the two fluo- 148 Dunbar and Jacobson xMAP™ 149 Table 1 Recommended Core Mutation Panel for General Population Cystic Fibrosis (CF) Carrier Screening Standard mutation panel ΔF508 ΔI507 G542X G551D W1282X N1303K R553X 621+1G→T R117H 1717-1G→A A455E R560T R1162X G85E R334W R347P 711+1G→T 1898+1G→A 2184delA 1078delT 3849+10kbC→T 2789+5G→A 3659delC 1148T 3120+1G→A Reflex tests I506Va I507Va F508Ca 5T/7T/9Tb a Benign variants. Login to comment
94 Methods The methods described below include: (1) design of oligonucleotide capture probes, (2) design of PCR amplification primers and multiplexed PCR reactions, (3) preparation of the probe-conjugated microsphere sets, (4) verification 150 Dunbar and Jacobson xMAPTM Table 2 Oligonucleotide Capture Probesa Target Microsphere Probe sequence Modificationb Sequence 5' → 3' set Standard mutation panel 1c I507 & F508 5'-AmMC12 AACACCAAAGATGATATTTT 006 2B DI507 5'-AmMC12 ACACCAAAGATATTTTCTT 008 3B DF508 5'-AmMC12 AAACACCAATGATATTTTC 015 4B W1282 5'-AmMC12 CAACAGTGGAGGAAAGCC 012 5B W1282X 5'-AmMC12 CAACAGTGAAGGAAAGCC 020 6 1717-1G 5'-AmMC12 TTGGTAATAGGACATCTCCA 017 7 1717-1GÆA 5'-AmMC12 TTGGTAATAAGACATCTCCA 019 8B G542 5'-AmMC12 TATAGTTCTTGGAGAAGGTGGA 026 9B G542X 5'-AmMC12 TATAGTTCTTTGAGAAGGTGGA 028 10C G551 & R553 5'-AmMC12 AGTGGAGGTCAACGAGCAA 038 11B G551D 5'-AmMC12 GTGGAGATCAACGAGCAA 030 12C R553X 5'-AmMC12 GTGGAGGTCAATGAGCAA 032 13 R560 5'-AmMC12 CTTTAGCAAGGTGAATAACT 035 14 R560T 5'-AmMC12 CTTTAGCAACGTGAATAACT 039 15 R117 5'-AmMC12 AGGAGGAACGCTCTATCGCG 042 16 R117H 5'-AmMC12 AGGAGGAACACTCTATCGCG 025 17B I148 5'-AmMC12 CTTCATCACATTGGAATGCAGA 034 18B I148T 5'-AmMC12 CTTCATCACACTGGAATGCAGA 045 19C 621+1G 5'-AmMC12 TTTATAAGAAGGTAATACTTCCT 046 20E 621+1G→T 5'-AmMC12 ATTTATAAGAAGTTAATACTTCCTT 048 21 N1303 5'-AmMC12 GGGATCCAAGTTTTTTCTAA 051 22 N1303K 5'-AmMC12 GGGATCCAACTTTTTTCTAA 052 23B 1078T 5'-AmMC12 CACCACAAAGAACCCTGA 054 24C 1078delT 5'-AmMC12 ACACCACAAGAACCCTGA 061 25 R334 5'-AmMC12 ATATTTTCCGGAGGATGATT 063 26 R334W 5'-AmMC12 ATATTTTCCAGAGGATGATT 064 27B R347 5'-AmMC12 ACCGCCATGCGCAGAACAA 067 28B R347P 5'-AmMC12 ACCGCCATGGGCAGAACAA 053 29C 711+1G 5'-AmMC12 ATTTGATGAAGTATGTACCTAT 059 30C 711+1G→T 5'-AmMC12 ATTTGATGAATTATGTACCTAT 071 31 G85 5'-AmMC12 TGTTCTATGGAATCTTTTTA 066 32B G85E 5'-AmMC12 ATGTTCTATGAAATCTTTTTA 073 33 3849+10kbC 5'-AmMC12 GTCTTACTCGCCATTTTAAT 077 34 3849+10kbC→T 5'-AmMC12 GTCTTACTCACCATTTTAAT 075 35 A455 5'-AmMC12 CCAGCAACCGCCAACAACTG 011 36D A455E 5'-AmMC12 TCCAGCAACCTCCAACAACTG 036 37 R1162 5'-AmMC12 TAAAGACTCGGCTCACAGAT 060 38 R1162X 5'-AmMC12 TAAAGACTCAGCTCACAGAT 068 39B 3659C 5'-AmMC12 TTGACTTGGTAGGTTTAC 022 40C 3659delC 5'-AmMC12 TTGACTTGTAGGTTTACC 079 41B 2789+5G 5'-AmMC12 TGGAAAGTGAGTATTCCATGTC 074 42D 2789+5G→A 5'-AmMC12 TTGGAAAGTGAATATTCCATGTC 014 43E 2184A 5'-AmMC12 GAAACAAAAAAACAATC 007 44E 2184delA 5'-AmMC12 AGAAACAAAAAACAATC 018 45B 1898+1G 5'-AmMC12 TATTTGAAAGGTATGTTCTTTG 013 (Continued) of microsphere coupling, (5) direct hybridization of biotinylated PCR amplification products to the multiplexed probe-coupled microsphere sets, and (6) results and data analysis. Login to comment
106 Table 3 Reverse Complementary Oligonucleotide Targetsa Target Target sequence Modification Sequence 5' → 3' Standard mutation panel C1b I507 & F508 5'-Biotin AAAATATCATCTTTGGTGTT C2 ΔI507 5'-Biotin AAAGAAAATATCTTTGGTGT C3 ΔF508 5'-Biotin AGAAAATATCATTGGTGTTT C4 W1282 5'-Biotin GGCTTTCCTCCACTGTTGC C5 W1282X 5'-Biotin GGCTTTCCTTCACTGTTGC C6 1717-1G 5'-Biotin TGGAGATGTCCTATTACCAA C7 1717-1G→A 5'-Biotin TGGAGATGTCTTATTACCAA C8 G542 5'-Biotin CCACCTTCTCCAAGAACTAT C9 G542X 5'-Biotin CCACCTTCTCAAAGAACTAT C10 G551 & R553 5'-Biotin CTTGCTCGTTGACCTCCACT C11 G551D 5'-Biotin CTTGCTCGTTGATCTCCACT C12 R553X 5'-Biotin CTTGCTCATTGACCTCCACT C13 R560 5'-Biotin AGTTATTCACCTTGATAAAG C14 R560T 5'-Biotin AGTTATTCACGTTGCTAAAG C15 R117 5'-Biotin CGCGATAGAGCGTTCCTCCT C16 R117H 5'-Biotin CGCGATAGAGTGTTCCTCCT C17 I148 5'-Biotin CTGCATTCCAATGTGATGAA C18 I148T 5'-Biotin CTGCATTCCAGTGTGATGAA C19 621+1G 5'-Biotin GGAAGTATTACCTTCTTATA C20 621+1G→T 5'-Biotin GGAAGTATTAACTTCTTATA C21 N1303 5'-Biotin TTAGAAAAAACTTGGATCCC C22 N1303K 5'-Biotin TTAGAAAAAAGTTGGATCCC C23 1078T 5'-Biotin CTCAGGGTTCTTTGTGGTGT C24 1078delT 5'-Biotin TCTCAGGGTTCTTGTGGTGT C25 R334 5'-Biotin AATCATCCTCCGGAAAATAT C26 R334W 5'-Biotin AATCATCCTCTGGAAAATAT C27 R347 5'-Biotin ATTGTTCTGCGCATGGCGGT C28 R347P 5'-Biotin ATTGTTCTGCCCATGGCGGT C29 711+1G 5'-Biotin TAGGTACATACTTCATCAAA C30 711+1G→T 5'-Biotin TAGGTACATAATTCATCAAA C31 G85 5'-Biotin TAAAAAGATTCCATAGAACA C32 G85E 5'-Biotin TAAAAAGATTTCATAGAACA C33 3849+10kbC 5'-Biotin ATTAAAATGGCGAGTAAGAC C34 3849+10kbC→T 5'-Biotin ATTAAAATGGTGAGTAAGAC C35 A455 5'-Biotin CAGTTGTTGGCGGTTGCTGG C36 A455E 5'-Biotin CAGTTGTTGGAGGTTGCTGG C37 R1162 5'-Biotin ATCTGTGAGCCGAGTCTTTA C38 R1162X 5'-Biotin ATCTGTGAGCTGAGTCTTTA (Continued) Rapid CF Screening by xMAPTM 153 Table 3 (Continued) Target Target sequence Modification Sequence 5' → 3' C39 3659C 5'-Biotin GGTAAACCTACCAAGTCAAC C40 3659delC 5'-Biotin AGGTAAACCTACAAGTCAAC C41 2789+5G 5'-Biotin ACATGGAATACTCACTTTCC C42 2789+5G→A 5'-Biotin ACATGGAATATTCACTTTCC C43 2184A 5'-Biotin AAGATTGTTTTTTTGTTTCT C44 2184delA 5'-Biotin AAGATTGTTTTTTGTTTCTG C45 1898+1G 5'-Biotin AAAGAACATACCTTTCAAAT C46 1898+1G→A 5'-Biotin AAAGAACATATCTTTCAAAT C47 3120+1G 5'-Biotin TTTTTACATACCTGGATGAA C48 3120+1G→A 5'-Biotin TTTTTACATATCTGGATGAA Reflex panel CR2 I506V 5'-Biotin GAAAATGTCATCTTTGGTGT CR3 I507V 5'-Biotin GAAAATATCGTCTTTGGTGT CR4 F508C 5'-Biotin AAAATATCATCTGTGGTGTT CR5 5T 5'-Biotin TCCCTGTTAAAAACACACAC CR6 7T 5'-Biotin CCCTGTTAAAAAAACACACA CR7 9T 5'-Biotin CCTGTTAAAAAAAAACACAC a The position and sequence of the mutation or variation is indicated in bold type. b Target C1 (I507 & F508) is also used in the reflex panel. Login to comment
114 Using a small target DNA (approx 100-300 bp) minimizes the potential for steric hindrance to affect the xMAPTM Table 4 PCR Amplification Primers Size CFTR target Mutation(s) Primer 5' Modification Sequence 5' → 3' (bp) Exon 10 ΔI507, ΔF508, BE10U 5'-Biotin TTCTGTTCTCAGTTTTCCTGG 107 I506V, I507V, E10D None TTGGCATGCTTTGATGACG F508C Exon 20 W1282X E20U None TTGAGACTACTGAACACTGAAGG 126 BE20D 5'-Biotin TTCTGGCTAAGTCCTTTTGC Intron 10 1717-1G→A E11U None TCAGATTGAGCATACTAAAAGTGAC 89 BE11D2 5'-Biotin GAACTATATTGTCTTTCTCTGCAAAC Exon 11 G542X, G551D, E11U2 None AAGTTTGCAGAGAAAGACAATATAG 135 R553X, R560T BE11D 5'-Biotin GAATGACATTTACAGCAAATGC Exon 4 R117H E4U None TTTGTAGGAAGTCACCAAAGC 145 BE4D2 5'-Biotin GAGCAGTGTCCTCACAATAAAGAG Exon 4/intron 4 I148T, E4U2 None CTTCTCTTTATTGTGAGGACACTGC 169 621+1G→T BE4D 5'-Biotin ATGACATTAAAACATGTACGATACAG Exon 21 N1303K BE21U 5'-Biotin TGCTATAGAAAGTATTTATTTTTTCTGG 106 E21D None AGCCTTACCTCATCTGCAAC Exon 7 1078delT, BE7U 5'-Biotin GAACAGAACTGAAACTGACTCG 199 R334W, R347P E7D3 None CAGGGAAATTGCCGAGTG Intron 5 711+1G→T I5U None CAACTTGTTAGTCTCCTTTCC 99 BI5D2 5'-Biotin AGTTGTATAATTTATAACAATAGTGC Exon 3 G85E E3U None CTGGCTTCAAAGAAAAATCC 117 BE3D2 5'-Biotin TGAATGTACAAATGAGATCCTTACC Chromosome 7 3849+10kbC→T BC7U 5'-Biotin GACTTGTCATCTTGATTTCTGG 148 C7D None TTTGGTGCTAGCTGTAATTGC Exon 9 A455E BE9U 5'-Biotin TCACTTCTTGGTACTCCTGTCC 105 E9D None CAAAAGAACTACCTTGCCTGC Exon 19-I R1162X BE19U 5'-Biotin ATTGTGAAATTGTCTGCCATTC 167 E19Da None CAATAATCATAACTTTCGAGAGTTG Exon 19-II 3659delC BE19U2 5'-Biotin TTTAAGTTCATTGACATGCCAAC 91 E19Da None CAATAATCATAACTTTCGAGAGTTG Intron 14B 2789+5G→A I14BU None GTGTCTTGTTCCATTCCAGG 147 BI14BD 5'-Biotin TGGATTACAATACATACAAACATAGTGG Exon 13 2184delA E13U None AGATGCTCCTGTCTCCTGG 126 BE13D 5'-Biotin TGCACAATGGAAAATTTTCGTATAG Intron 12 1898+1G→A I12U None TTAGACTCTCCTTTTGGATACC 110 BI12D 5'-Biotin GTCTTTCTTTTATTTTAGCATGAGC Intron 16 3120+1G→A I16U None ATGACCTTCTGCCTCTTACC 118 BI16D 5'-Biotin ATGAAAACAAAATCACATTTGC Intron 8 5T/7T/9T I8U None TAATGGATCATGGGCCATGTGC 212 BI8D 5'-Biotin ACTGAAGAAGAGGCTGTCATCACC CFTR, cystic fibrosis transmembrane conductance regulator gene. Login to comment
119 Coriell Cell Repositories, NA12960 ΔI507/R347P Patient sample G551D/R347P Coriell Cell Repositories, NA12785 621+1G→T/711+1G→T Coriell Cell Repositories, NA11280 621+1G→T/G85E Coriell Cell Repositories, NA11282 3849+10kbC→T/3849+10kbC→T Coriell Cell Repositories, NA11860 A455E/normal Patient sample 621+1G→T/A455E Coriell Cell Repositories, NA11290 R1162X/normal Coriell Cell Repositories, NA12585 ΔF508/3659delC Coriell Cell Repositories, NA11275 2789+5G→A/2789+5G→A Coriell Cell Repositories, NA11859 2184delA/normal Patient sample 1898+1G→A/normal Patient sample 621+1G→T/3120+1G→A Coriell Cell Repositories, NA07441 3120+1G→A/3120+1G→A Patient sample F508C/normal Coriell Cell Repositories, NA13033 I506V/normal Coriell Cell Repositories, NA13032 R347H/normal Patient sample ΔF508/3120G→A Patient sample S549N/normal Patient sample S549R/normal Patient sample CFTR, cystic fibrosis transmembrane conductance regulator gene. Login to comment

PMID: 15698946 [PubMed] des Georges M et al: "High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France."

No. Sentence Comment

38 The 20 most common mutations responsible for CF worldwide were investigated by amplification refractory mutation system (ARMS) and migration on agarose gel (Kit Elucigene CF20, including mutations c.1717-1GNA, p.G542X, p.W1282X, p.N1303K, p.F508del, c.3849+10kbCNT, c.621+1GNT, p.R553X, p.G551D, p.R117H, p.R1162X, p.R334W, p.A455E, c.2183AANG, c.3659delC, c.1078delT, p.I507del, p.R347P, p.S1251N, p.E60X). Login to comment
131 The panel of 30 mutations (c.1717-1GNA, p.G542X, p.W1282X, p.N1303K, p.F508del, c.3849+10kbCNT, c.621+1GNT, p.R553X, p.G551D, p.R117H, p.R1162X, p.R334W, p.A455E, c.2183AANG, c.3659delC, c.1078delT, p.I507del, p.R347P, p.S1251N, p.E60X, p.Y1092X, c.394delTT, c.1811+1.6kbANG, c.3272-26ANG, c.2789+5GNA, c.3120+1GNA, c.711+ 1GNT, p.G85E, p.Y122X, p.W846X) should account for 83.32% of the CF alleles in L-R and 84.25% in the whole country. Login to comment

PMID: 15507674 [PubMed] Hadd AG et al: "Microsphere bead arrays and sequence validation of 5/7/9T genotypes for multiplex screening of cystic fibrosis polymorphisms."

No. Sentence Comment

197 Intron 8 Genotype by Coriell Number, Characterized CF Mutation and Allele Fraction for 5/7/9T Intron 8 genotype Coriell sample Characterized mutation Allele fraction by probe 5T 7T 9T 7T/7T NA09947 Normal 0.04 0.93 0.03 NA11277 ⌬I507/normal 0.06 0.90 0.04 NA11761 G551D/R553X 0.06 0.92 0.02 NA11859 2789ϩ5GϾA/2789ϩ5GϾA 0.02 0.96 0.02 NA11860 3849ϩ10kbCϾT/3849ϩ10kbCϾT 0.03 0.94 0.03 NA12444 1717-1GϾT/normal 0.06 0.87 0.07 NA12585 R1162X/normal 0.07 0.86 0.08 NA12785 R347P/G551D 0.04 0.92 0.05 NA12960 R334W/normal 0.06 0.92 0.02 NA12961 V520F/normal 0.06 0.89 0.05 NA13033 F508C/normal 0.03 0.93 0.04 9T/9T NA01531 ⌬F508/⌬F508 0.14 0.04 0.82 NA11281 621ϩ1GϾT/⌬F508 0.14 0.04 0.82 NA11283 A455E/⌬F508 0.13 0.05 0.82 NA11290 A455E/621ϩ1GϾT 0.12 0.01 0.87 NA11496 G542X/G542X 0.14 0.05 0.81 5T/7T NA11723 W1282X/normal 0.53 0.44 0.03 NA13032 I506V/normal 0.58 0.39 0.03 5T/9T NA11279 129GϾC/⌬F508 0.51 0.00 0.49 NA13591 R117H/⌬F508 0.52 0.00 0.48 7T/9T NA07441 3120ϩ1GϾA/621ϩ1GϾA 0.08 0.41 0.51 NA07552 R553X/⌬F508 0.09 0.36 0.55 NA07830 556dA/⌬F508 0.11 0.37 0.52 NA11275 3659dC/⌬F508 0.10 0.37 0.53 NA11278 Q493X/⌬F508 0.09 0.38 0.53 NA11280 711ϩ1GϾT/621ϩ1GϾA 0.09 0.37 0.54 NA11282 G85E/621ϩ1GϾA 0.07 0.39 0.53 NA11284 R560T/⌬F508 0.08 0.39 0.52 NA11472 N1303K/G1349D 0.08 0.39 0.54 Figure 3. Login to comment

PMID: 15463906 [PubMed] Dugueperoux I et al: "Cystic fibrosis at the Reunion Island (France): spectrum of mutations and genotype-phenotype for the Y122X mutation."

No. Sentence Comment

75 G 1 (0.68) DeltaF508/A455E 1 (1.49) 2789 + 5G ! Login to comment
76 A 1 (0.68) DeltaF508/ D993Y 1 (1.49) 993del5 1 (0.68) DeltaF508/ G542X 1 (1.49) A455E 1 (0.68) DeltaF508/2183AA ! Login to comment

PMID: 15181620 [PubMed] Maisonneuve P et al: "Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation."

No. Sentence Comment

26 Of Ͼ1000 identified mutations in the CFTR gene, only 25 proven disease-causing mutant alleles (⌬F508, G551D, G542X, R553X, W1282X, R347P, NI303K, R560T, ⌬I507, 1717-1GϾA, A455E, 3120ϩ1GϾA, 621ϩ1GϾT, R117H, 711ϩ1GϾT, R1162X, 3849ϩ10kbCϾT, 2789ϩ5GϾT, R334W, G85E, 1078delT, 1898ϩ1GϾT, 2184delA, 3659delC, and I148T) are recommended by the American College of Medical Genetics for routine diagnostic and carrier testing.16 Most of these are routinely recorded in the CFF registry, but rarer mutations can be recorded if identified by more comprehensive testing. Login to comment
28 Patients were classified according to their genotype: those carrying 2 severe mutations (⌬F508, ⌬I507, G542X, G551D, N1303K, R553X, R560T, R1162X, W1282X, 621ϩ1GϾT, 711ϩ1GϾT, 1717-1GϾA, 2184delA, and 3659delC), which generally are associated with pancreas insufficiency (PI); and those carrying at least 1 mild mutation (3849ϩ10kbCϾT, R117H, 2789ϩ5GϾA, R347P, R334W, and A455E), which are generally associated with PS. Login to comment
42 The greatest frequency of pancreatitis was reported in patients carrying at least 1 R334W mutation (19.0%), followed by patients with a 2789ϩ5GϾA mutation (14.9%), R117H mutation (11.7%), R347P mutation (11.6%), 3849ϩ10kbCϾT mutation (9.0%), A455E mutation (8.3%), or G85E mutation (8.0%; Table 1). Login to comment
64 of patients Patients with pancreatitis At least 1 attack of pancreatitis Ն2 attacks of pancreatitis All genotyped patients with CF 17,871 364 (2.0) - - Pancreas insufficienta 12,997 114 (0.9) 1.0 (reference) 1.0 (reference) Pancreas sufficientb 868 103 (11.9) 9.3 (6.7-12.8) 14.8 (8.2-26.8) 3849ϩ10kbCϾT/anyc 256 23 (9.0) 5.3 (3.1-9.0) 7.1 (2.8-18.3) R117H/anyc 249 29 (11.7) 8.9 (5.5-14.5) 14.1 (6.1-32.7) 2789ϩ5GϾA/anyc 134 20 (14.9) 13.2 (7.3-23.8) 10.4 (3.1-35.5) R347P/anyc 95 11 (11.6) 11.1 (5.3-23.1) 26.6 (9.1-77.4) R334W/anyc,d 79 15 (19.0) 25.8 (13.2-50.5) 43.6 (15.3-124) A455E/anyc 60 5 (8.3) 3.4 (2.6-4.4) 18.3 (5.0-67.9) Genotype incompletely determinede 4006 147 (3.7) 3.4 (2.6-4.4) 6.3 (3.8-10.5) NOTE. Values expressed as number (percent) or odds ratio (95% confidence interval). Login to comment
68 bPatients with pancreas sufficiency (PS) carrying at least 1 PS mutation (3849ϩ10kbCϾT, R117H, 2789ϩ5GϾA, R347P, R334W, A455E). Login to comment

PMID: 12458151 [PubMed] Powell K et al: "Therapeutic approaches to repair defects in deltaF508 CFTR folding and cellular targeting."

No. Sentence Comment

97 Class V defects (3849 1 10 kB C → T, A455E, by lowering the incubation temperature for cell 2789 1 5G → A) lead to a reduction in the pro-growth, the CFTR may attain a conformation that duction of CFTR, although residual product reaches allows it to escape from degradation in the ER and the surface and is functionally operational. Login to comment
98 Class V defects (3849 1 10 kB C ࢐ T, A455E, by lowering the incubation temperature for cell 2789 1 5G ࢐ A) lead to a reduction in the pro-growth, the CFTR may attain a conformation that duction of CFTR, although residual product reaches allows it to escape from degradation in the ER and the surface and is functionally operational. Login to comment

PMID: 12454843 [PubMed] Durno C et al: "Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis."

No. Sentence Comment

105 CFTR Genotypes Among CF Patients With PS With and Without Pancreatitis Two mutations (n) ⌬F508/R117H (9) ⌬F508/(5T) (6) ⌬F508/3272-26A 3 G (4) ⌬F508/R347H (2) ⌬F508/P574H (2) ⌬F508/875 ϩ 1G Ͼ C (2) ⌬F508/3849 ϩ 10kb C 3 T (1) ⌬F508/A455E (1) ⌬F508/D614G (1) ⌬F508/G85E (1) ⌬F508/R347P (1) ⌬F508/S1251N (1) ⌬F508/⌬F508a (1) ⌬F508/3120G Ͼ A (1) ⌬F508/G551Da (1) G542X/R117H (1) R560T/L206W (1) R117H/R117H (1) R31L/P67L (1) 1461ins4 (AGAT)/G85E (1) G551D/(5T) (1) R1066C/3849 ϩ 10kb C Ͼ T (1) G551D/3849 ϩ 10kb C Ͼ T (1) R334W/R334W (1) R334W/681delC (1) W1282X/3489 ϩ 10kb C Ͼ T (1) One mutation (n) ⌬F508/- (18) L1077P/- (1) W1282X/- (1) M1137V/- (1) G551D/- (1) R347H/- (1) Q30X1/- (1) G1244E/- (1) R117H/- (1) 621 ϩ 2G621 ϩ 1G 3 T/- (1) NOTE. Login to comment
124 of episodes of pancreatitis Genotype 1 0.3 12 21.7 2 ⌬F508/S1251N 2 0.3 34 30.0 1 ⌬F508/R347H 3 4.4 13 42.5 3 / 4 4.4 21 36.5 1 ⌬F508/ 5 7.3 26 40.8 10 ⌬F508/P67L 6 9.6 29 29.9 (D) 1 ⌬F508/ 7 12.0 18 39.9 1 ⌬F508/R347P 8 12.9 37 40.9 2 G542X/D1152H 9 13.0 30 50.3 1 ⌬F508/3849 ϩ 10Kbc Ͼ T 10 14.7 13 21.5 1 DF508/R117H 11 15.6 34 40.8 1 ⌬F508/2789ϩ5G Ͼ T 12 15.6 10 26.0 10 ⌬F508/R117H 13 16.0 10 22.0 14 ⌬F/508/3849 ϩ 10kbC Ͼ T 14 16.0 18 21.2 (D) 1 R1066C/3849 ϩ 10kbC Ͼ T 15 19.9 15 40.8 5 No DNA 16 23.2 19 23.2 15 ⌬F508/11234V 17 24.1 40 47.6 (D) 1 No DNA 18 26.9 25 43.3 12 No DNA 19 27.4 35 50.3 (D) 2 ⌬F508/A455E NOTE. Login to comment

PMID: 12079272 [PubMed] Naruse S et al: "Cystic fibrosis and related diseases of the pancreas."

No. Sentence Comment

62 is observed only when normal CFTR function is less than 1%.13 In general, patients with pancreatic insuciency are homozygous or compound heterozygous for two severe mutations (class I, II or III in Figure 3), such as DF508, DI507, Q493X, G542X, R553X, W1282X, 621 1G 4 T, 1717-1G 4 A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T, whereas the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H (class IV or V).5,20 EXOCRINE PANCREAS IN CYSTIC FIBROSIS Pathology of the pancreas in CF There is a spectrum of pancreatic abnormalities in CF irrespective of age.21,22 Pancreatic lesions may be absent in an individual case, but in long-standing CF the pancreas is small, hard and nodular with increased fat and multiple cysts; hence the name `cystic ®brosis of the pancreas'. Login to comment
64 is observed only when normal CFTR function is less than 1%.13 In general, patients with pancreatic insuQciency are homozygous or compound heterozygous for two severe mutations (class I, II or III in Figure 3), such as DF508, DI507, Q493X, G542X, R553X, W1282X, 621 W 1G 4 T, 1717-1G 4 A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T, whereas the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H (class IV or V).5,20 EXOCRINE PANCREAS IN CYSTIC FIBROSIS Pathology of the pancreas in CF There is a spectrum of pancreatic abnormalities in CF irrespective of age.21,22 Pancreatic lesions may be absent in an individual case, but in long-standing CF the pancreas is small, hard and nodular with increased fat and multiple cysts; hence the name `cystic &#ae;brosis of the pancreas'. Login to comment

PMID: 10766983 [PubMed] Restrepo CM et al: "CFTR mutations in three Latin American countries."

No. Sentence Comment

34 The isolated DNA from each patient was amplified by polymerase chain reaction (PCR) using a kit for reverse dot blot detection of 16 common CF mutations: ⌬F508, R553X, G542X, G551D, N1303K, W1282X, R117H, R334W, R347P, A455E, ⌬I507, 1717-1 G>A, R560T, 3849+10kb C>T, 621+1 G>T, S549N [Villalobos-Torres et al., 1997]. Login to comment

PMID: 10923036 [PubMed] Claustres M et al: "Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France."

No. Sentence Comment

103 b 3905insT, 1811+1.6kbA>G, S945L, S1251N, Y122X, 2711delT, R117H, E60X, 2184insA, E585X, L558S, S1235R, D1152H, K710X, Q493X, A455E, G178R, I148T, 574delA. Login to comment
141 Some mutants are misprocessed (class II) but generate channels that retain significant activity which is sufficient to confer a milder clinical phenotype (for instance, A455E or P574H). Login to comment
152 Twenty-four non F508del mutations were found associated with the 9T allele: 394delTT, L90S, D110H, R117G, 621+1G>T, V232D, A455E, G542X, R851L, T908N, 2789+5G>A, 2896insAG, H939R, 3007delG, I980K, I1027T, R1066H, A1067T, D1154G, 3737delA, R74W+D1270N, N1303I, N1303K, D1377H. Login to comment

PMID: 10228103 [PubMed] Jorissen MB et al: "Genotype-phenotype correlations for the paranasal sinuses in cystic fibrosis."

No. Sentence Comment

16 The mutation ⌬F508, associated with pancreatic insufficiency and diagnosis at younger age, is classified as a "severe" mutation (6), whereas others such as R117H and A455E are considered to be "mild" mutations. Login to comment
17 A455E also correlated with better lung function (7); a correlation between ⌬F508 and lung function was not found (8, 9). Login to comment
93 Three of them had a mild mutation (R117H or A455E) and were clinically classified as class 0 (n ϭ 2) or class 1 (n ϭ 1). Login to comment
94 The fourth patient had undergone sinus surgery and was ⌬F508 negative (G542X/unidentified). Login to comment
120 of Patients in Surgical Group ⌬F508 Genotype Homozygosity 69 61 22 Compound heterozygosity 33 29 5 Negative 11 10 1 Mutations ⌬F508 171 75.7 27 Non-⌬F508 55 24.3 6 R117H (4) C276X (1) 394delT (1) W401X (2,† ) A455E (1) G542X (4,‡ ) G551D (1) R553X (1) G628R(G→C) (1) Y1092X (1) D1152H (1) S1251N (1) W1282X (3) N1303K (8) W1310X (1) 1717-1G→A (3,† ) 1898ϩ1G→C (1) 2183AA-G (3,†† ) 3659delC (2) 3272-26A→G (2,† ) 4218-insT (2) unknown (11,‡ ) * The genotype and mutations are given for the 113 patients with CF. Login to comment
121 of Patients in Surgical Group DF508 Genotype Homozygosity 69 61 22 Compound heterozygosity 33 29 5 Negative 11 10 1 Mutations DF508 171 75.7 27 Non-DF508 55 24.3 6 R117H (4) C276X (1) 394delT (1) W401X (2,ߤ ) A455E (1) G542X (4,ߥ ) G551D (1) R553X (1) G628R(G࢐C) (1) Y1092X (1) D1152H (1) S1251N (1) W1282X (3) N1303K (8) W1310X (1) 1717-1G࢐A (3,ߤ ) 189811G࢐C (1) 2183AA-G (3,ߤߤ ) 3659delC (2) 3272-26A࢐G (2,ߤ ) 4218-insT (2) unknown (11,ߥ ) * The genotype and mutations are given for the 113 patients with CF. Login to comment

PMID: 10232317 [PubMed] Johnson DW et al: "Sunshine, sweating, and main d'accoucheur."

No. Sentence Comment

16 Screening for ten of the common cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations (⌬F508, G551D, R553X, G542X, N1303K, A455E, 621+1, Delta I507 and R117H), showed a single delta F508 mutation. Login to comment

PMID: 9797105 [PubMed] Jarvi K et al: "Heterogeneity of reproductive tract abnormalities in men with absence of the vas deferens: role of cystic fibrosis transmembrane conductance regulator gene mutations."

No. Sentence Comment

60 of men Single mutation 5T /Unknown 13 ⌬F508 /Unknown 8 R117H /Unknown 2 W1282X /Unknown 1 4016insT /Unknown 1 N1303K /Unknown 1 Total 26 Two mutations ⌬F508 /5T 4 ⌬F508 /R117H 2 ⌬F508 /R75Q 1 5T /2183AA3G 1 5T /N1303K 1 5T /G542X 1 R117H /G551A 1 R117H /2184insA 1 A455E /3849ϩ10KbC 1 3T Total 13 No mutations 7 Total no. Login to comment

PMID: 9674722 [PubMed] Schwiebert EM et al: "Cystic fibrosis: a multiple exocrinopathy caused by dysfunctions in a multifunctional transport protein."

No. Sentence Comment

223 They include another deletion mutation at amino acid position 507 (⌬I507), several missense mutations (F508C, G551D, G551S, A455E, R553Q, P574H, S549N, A559T), and some nonsense mutations (G542X, R553X, Q493X). Login to comment
238 Some of these mutations, however, such as A455E, P574H and G551S have been associated either with less severe pulmonary disease and/or less compromised Cl- channel function. Login to comment
239 A455E causes only a subtle decrease in CFTR Cl- channel activity and fails to prevent regulatory interaction with ORCCs (88). Login to comment

PMID: 9591500 [PubMed] Tuerlings JH et al: "Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection."

No. Sentence Comment

2 The three most frequent cystic fibrosis (CF)-causing CFTR mutations in the Dutch population (⌬F508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens (CBAVD) in the Dutch population (⌬F508, R117H, and IVS8-5T) were analyzed. Login to comment
65 The three most frequent CFTR mutations causing CF in the Dutch population (⌬F508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens in the Dutch population (⌬F508, R117H, and IVS8-5T) were analyzed. Login to comment
68 Detection of R117H, A455E, and G542X mutations was performed with the use of allele-specific amplification tests, as described by Ferrie et al. (12) for G542X and R117H. Login to comment
69 For the A455E mutation, the following primers were designed (mismatch in lower case): AEC: 5Ј-GACACTACACCCATACATTCTCCTAATG-3Ј, AEM: 5Ј-TCAAGATAGAAAGAGGACAGTTGTTGtA-3Ј, and AEN: 5Ј-TCAAGATAGAAAGAGGACAGTTGTTG- GC-3Ј. Login to comment
92 For the A455E, G542X, and ⌬I507 mutations, the frequency in the normal population was based on the 3.3% carrier frequency and the locally derived relative frequencies of mutations in CF patients (H.S., unpublished data). Login to comment
132 Mutation General population* (95% CI) Patients with OAT† (95% CI) Patients with CBAVD‡ Patients with CF§ ⌬F508 0.013 (0.011-0.015) 0.013 (0.0037-0.047) 0.169 0.777 R117H 0.009 (0.0027-0.030) 0.006 (0.0012-0.037) 0.305 Ͻ0.001 IVS8-5T 0.037 (0.019-0.073) 0.006 (0.0012-0.037) 0.055 ND A455E Ͻ0.001 (ND) 0 (ND) Ͻ0.001 0.026 G542X Ͻ0.001 (ND) 0 (ND) Ͻ0.001 0.015 ⌬I507 Ͻ0.001 (ND) 0 (ND) Ͻ0.001 Ͻ0.001 Total 0.005 (ND)࿣ 0.027 (0.010-0.067) 0.529 0.818 Note: OAT ϭ oligoasthenoteratozoospermia; CBAVD ϭ congenital bilateral absence of the vas deferens; ND ϭ not done. Login to comment
133 * Locally derived frequencies for ⌬F508, R117H, and IVS8-5T (n ϭ 21,544 chromosomes, n ϭ 232 chromosomes, and n ϭ 212 chromosomes, respectively); and theoretical estimates for A455E, G542X, and ⌬I507 based on a 3.3% carrier frequency and regionally derived mutation frequencies (H.S., unpublished data). Login to comment
136 § H.S., unpublished data (n ϭ 726 for ⌬F508, A455E, and G542X; n ϭ 272 for R117H; IVS8-5T not determined). Login to comment

PMID: 9499426 [PubMed] Mickle JE et al: "A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis."

No. Sentence Comment

151 Mutation analysis Total genomic DNA was assayed for 16 common CFTR mutations (R117H, 621+1G→T, R334W, R349P, A455E, 1717-1G→A, ∆I507, ∆F508, G542X, S549N, G551D, R553X, R560T, 3849+10 kb C→T, W1282X, N1303K) by reverse dot-blot hybridization (46). Login to comment
152 Mutation analysis Total genomic DNA was assayed for 16 common CFTR mutations (R117H, 621+1G࢐T, R334W, R349P, A455E, 1717-1G࢐A, ࢞I507, ࢞F508, G542X, S549N, G551D, R553X, R560T, 3849+10 kb C࢐T, W1282X, N1303K) by reverse dot-blot hybridization (46). Login to comment

PMID: 9541118 [PubMed] De Braekeleer M et al: "Is meconium ileus genetically determined or associated with a more severe evolution of cystic fibrosis?"

No. Sentence Comment

16 Although the A455E mutation is Table 1 Distribution of meconium ileus among CFTR genotypes in Saguenay Lac-Saint-Jean No of CF Proportion No of CFpatients Proportion Proportion ofMI Genotypes patients (%) with meconium ileus (%) among genotypes AF508/AF508 52 39.4 5 26.3 9.6 AF508/621+G-*T 34 25.8 9 47.4 26.5 AF508/A455E 14 10.6 0 0.0 0.0 621+1G-*T/A455E 8 6.1 0 0.0 0.0 621+1G-*T/G85E 2 1.5 1 5.3 50.0 621+1G-*T/Y1092X 1 0.8 0 0.0 0.0 AF508/Y1092X 4 3.0 1 5.3 25.0 A455E/R117C 1 0.8 0 0.0 0.0 AF508/I148T 2 1.5 0 0.0 0.0 621+1G-*T/ 4 3.0 0 0.0 0.0 711 +1G-*T 621+1G-4T/S489X 1 0.8 0 0.0 0.0 AF508/Q890X 1 0.8 1 5.3 100.0 621+1G->T/ 6 4.5 2 10.5 33.3 621+1G-sT AF508/unknown 1 0.8 1 5.3 100.0 Unknown/unknown 1 0.8 0 0.0 0.0 Table 2 Main clinicalfindings in patients with meconium ileus With MI Without MI p value No of patients 18 18 Sex (M/IF) 6/12 6/12 No of patients alive 16 17 Mean age (SD) 16.75 (9.7) 16.70 (7.9) p=0.99 Mean birth weight (SD) 3.24 (0.40) 3.02 (0.47) p=O.18 Mean birth height (SD) 50.0 (2.27) 50.0 (2.58) p=0.86 Currentweightcentile (SD) 26.7 (24.5) 14.1 (18.0) p=0.06 Current height centile (SD) 29.9 (25.1) 20.6 (25.6) p=0.33 Sweat chloride concentration (mEq/l) 105.9 (6.5) 101.1 (9.8) p=O.12 Mean FVC (SD) 89.7 (24.4) 93.0 (17.0) p=0.75 Mean FEV (SD) 73.1 (23.9) 75.4 (18.7) p=0.81 Mean Shwachman score (SD) 82.8 (11.8) 79.2 (12.6) p=0.36 Colonisation with Pseudomonas aeruginosa 13 14 p=0.70 Staphyloccoccus aureus 16 17 p=0.55 Haemophilus influenzae 13 14 p=0.70 Pseudomonas maltophilia 4 6 p=0.46 Pseudomonas cepacia 0 1 Pancreatic insufficiency 18 18 DIOS 7 1 p=0.016 Rectal prolapse 1 2 p=0.55 Recurrent abdominal pain 6 1 p=0.035 Diabetes mellitus 5 0 p=0.016 Liver complications 3* 0 p=0.07 Nasal polyposis 6 6 p=1.00 DIOS=distal intestinal obstruction syndrome. Login to comment
18 considered to be a "mild" mutation, 13 ofthe 22 patients from SLSJ carrying a AF508/ A455E or a 621+1G-4T/A455E genotype had PI.5 However, none ofthem had MI. Login to comment
51 5 De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment
52 5 De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment

PMID: 9476862 [PubMed] Rubenstein RC et al: "A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function."

No. Sentence Comment

181 Measurement of the NPD in five CF patients with another partially functional CFTR mutation, A455E (substitution of glutamate for alanine at position 455) have recently been published (26). Login to comment
184 It is possible, even though R117H and A455E are both partially functional CFTR mutations, that their interactions with other (as yet undetermined) cellular constituents might differ, and thereby alter NPD responses. Login to comment

PMID: 9559222 [PubMed] De Braekeleer M et al: "Correlation of sweat chloride concentration with genotypes in cystic fibrosis patients in Saguenay Lac-Saint-Jean, Quebec, Canada."

No. Sentence Comment

3 Results: CF patients carrying the A455E mutation, usually associated with pancreatic sufficiency, had lower sweat chloride concentrations than those carrying mutations associated with pancreatic insufficiency (⌬F508 and 621ϩ1G3T). Login to comment
25 Three CFTR mutations account for 93.7% of the CF chromosomes; these are the ⌬F508 (63.4%), 621ϩ1G3T (22.3%), and A455E (8%) mutations. Login to comment
28 All the 114 CF patients in the present study had pancreatic insufficiency but 7 with a A455E/⌬F508 genotype, 2 with a A455E/621ϩ1G3T genotype and 1 with a R177C/A455E genotype who were pancreatic sufficient. Login to comment
38 Patients with the A455E/⌬F508 or the 621ϩ1G3T/ A455E genotype had significantly lower chloride values than those homozygous for the ⌬F508 mutation (p Ͻ 0.05). Login to comment
40 A significant difference was also found between CF patients carrying the A455E mutation on one chromosome and the ⌬F508 or 621ϩ1G3T mutation on the other chromosome (p Ͻ 0.05). Login to comment
41 There were no significant differences in sweat chloride values between patients homozygous for the ⌬F508 mutation and those having a ⌬F508/ 621ϩ1G3T genotype or being hemizygous for the Y1092X or 711ϩ1G3T mutation (p Ͼ 0.05). Login to comment
44 It was the result of significant differences between the A455E group and the other two groups, ⌬F508 and 621ϩ1G3T (p Ͻ 0.05). Login to comment
45 Patients were classified as hemizygous for the ⌬F508 mutation if the other chromosome did not carry the 621ϩ1G3T, nor the A455E mutation. Login to comment
46 Patients carrying the A455E mutation on one chromosome were included in the A455E mutation category, independently of the second mutation. Login to comment
48 Pancreatic insufficiency (PI) is obtained TABLE 1 Sweat Chloride Concentrations by Genotype or Mutation Among CF Patients in SLSJ Genotype No. of Patients Mean Chloride Concentration (mEq/L) (SD) Minimum Value (mEq/L) Maximum Value (mEq/L) ⌬F508/⌬F508 47 102.77 (8.43) 77 119 621ϩ1G3T/⌬F508 28 103.5 (7.4) 87 120 621ϩ1G3T/A455E 6 94.17 (10.87) 74 106 A455E/⌬F508 12 77.08 (18.48) 54 107 Y1092X/⌬F508 or 621ϩ1G3T 5 100.6 (11.67) 87 117 621ϩ1G3T/621ϩ1G3T 5 112.4 (2.97) 108 116 621ϩ1G3T/711ϩ1G3T 4 106.5 (4.12) 102 110 ⌬F508/other 3 102.33 (11.5) 91 114 Other/other 2 71 62 80 621-other 2 89.5 84 95 Mutation No. of Patients Mean Chloride Concentration (mEq/L) (SD) Minimum Value (mEq/L) Maximum Value (mEq/L) ⌬F508 54 102.28 (8.56) 77 119 621ϩ1G3T 40 104.55 (8.14) 84 120 A455E 19 81.68 (18.14) 54 107 when a CF patient has two 'severe` alleles with respect to the exocrine pancreatic function (⌬F508 being one of them). Login to comment
51 However, the follow-up of CF patients with one mild allele (A455E) has shown that some PS patients may develop pancreatic insufficiency at a later stage of the disease (14). Login to comment
58 Class IV mutations result in a reduction in the amount of chloride current (e.g., R117H, R347P, S1251N mutations) while class V mutations result in a reduction in the amount of a normally functioning CFTR protein (e.g., A455E, 3849ϩ10kbC3T mutations). Login to comment
65 It was the case for ⌬F508/⌬F508 versus 621ϩ1G3T/621ϩ1G3T or A455E/⌬F508 versus A455E/621ϩ1G3T. Login to comment
69 Simone Aubin, Claudette La- rochelle and Suzanne Mignault from the Clinique de TABLE 2 Distribution of the Mean Sweat Chloride Concentration by Genotype Genotype No. of CF Patients Mean Chloride Concentration (mmol/L) (SD) Pancreatic Status References G542X/⌬F508 128 109 (23) Pl 18 R553X/⌬F508 46 105 (18) Pl 18 N1303K/⌬F508 56 104 (24) Pl 18 W1282X/⌬F508 13 110 (18) Pl 18 1717-1G3A/⌬F508 26 107 (36) Pl 18 621ϩ1G3T/⌬F508 22 100 (20) Pl 18 R117H/⌬F508 20 82 (19) PS 18 ⌬F508/⌬F508 328 106 (22) Pl 18 3849ϩ10kb C3T/⌬F508 6 61 (11) PS 19 3849ϩ10kb C3T/⌬F508 9 41 (12) PS (6) 20 R347P/⌬F508 5 100 (26) Pl 21 R334W/⌬F508 10 108 (19) Pl (6) 22 1811ϩ1.6kb A3C/⌬F508a 17 98 (12) Pl 23 3905insT/⌬F508 7 124 Pl 24 W1282X/W1282X 16 113 (12) Pl 25 W1282X/⌬F508 22 109 (11) Pl 25 G551D/⌬F508 58 101 (16) Pl 26 R1162X/R1162X 9 99 (13) Pl 27 1949del84/⌬F508 4 105 (20) Pl 28 ⌬F508/⌬F508 47 103 (8) Pl This study 621ϩ1G3T/⌬F508 28 103 (7) Pl This study 621ϩ1G3T/A455E 6 94 (11) Pl/PS This study A455E/⌬F508 12 77 (18) Pl/PS This study a Or other 'severe` mutations. Login to comment
39 Patients with the A455E/DF508 or the 62111G3T/ A455E genotype had significantly lower chloride values than those homozygous for the DF508 mutation (p , 0.05). Login to comment
47 Patients were classified as hemizygous for the DF508 mutation if the other chromosome did not carry the 62111G3T, nor the A455E mutation. Login to comment
50 Pancreatic insufficiency (PI) is obtained TABLE 1 Sweat Chloride Concentrations by Genotype or Mutation Among CF Patients in SLSJ Genotype No. of Patients Mean Chloride Concentration (mEq/L) (SD) Minimum Value (mEq/L) Maximum Value (mEq/L) DF508/DF508 47 102.77 (8.43) 77 119 62111G3T/DF508 28 103.5 (7.4) 87 120 62111G3T/A455E 6 94.17 (10.87) 74 106 A455E/DF508 12 77.08 (18.48) 54 107 Y1092X/DF508 or 62111G3T 5 100.6 (11.67) 87 117 62111G3T/62111G3T 5 112.4 (2.97) 108 116 62111G3T/71111G3T 4 106.5 (4.12) 102 110 DF508/other 3 102.33 (11.5) 91 114 Other/other 2 71 62 80 621-other 2 89.5 84 95 Mutation No. of Patients Mean Chloride Concentration (mEq/L) (SD) Minimum Value (mEq/L) Maximum Value (mEq/L) DF508 54 102.28 (8.56) 77 119 62111G3T 40 104.55 (8.14) 84 120 A455E 19 81.68 (18.14) 54 107 when a CF patient has two 'severe` alleles with respect to the exocrine pancreatic function (DF508 being one of them). Login to comment
53 However, the follow-up of CF patients with one mild allele (A455E) has shown that some PS patients may develop pancreatic insufficiency at a later stage of the disease (14). Login to comment
60 Class IV mutations result in a reduction in the amount of chloride current (e.g., R117H, R347P, S1251N mutations) while class V mutations result in a reduction in the amount of a normally functioning CFTR protein (e.g., A455E, 3849110kbC3T mutations). Login to comment
67 It was the case for DF508/DF508 versus 62111G3T/62111G3T or A455E/DF508 versus A455E/62111G3T. Login to comment
71 Simone Aubin, Claudette Larochelle and Suzanne Mignault from the Clinique de TABLE 2 Distribution of the Mean Sweat Chloride Concentration by Genotype Genotype No. of CF Patients Mean Chloride Concentration (mmol/L) (SD) Pancreatic Status References G542X/DF508 128 109 (23) Pl 18 R553X/DF508 46 105 (18) Pl 18 N1303K/DF508 56 104 (24) Pl 18 W1282X/DF508 13 110 (18) Pl 18 1717-1G3A/DF508 26 107 (36) Pl 18 62111G3T/DF508 22 100 (20) Pl 18 R117H/DF508 20 82 (19) PS 18 DF508/DF508 328 106 (22) Pl 18 3849110kb C3T/DF508 6 61 (11) PS 19 3849110kb C3T/DF508 9 41 (12) PS (6) 20 R347P/DF508 5 100 (26) Pl 21 R334W/DF508 10 108 (19) Pl (6) 22 181111.6kb A3C/DF508a 17 98 (12) Pl 23 3905insT/DF508 7 124 Pl 24 W1282X/W1282X 16 113 (12) Pl 25 W1282X/DF508 22 109 (11) Pl 25 G551D/DF508 58 101 (16) Pl 26 R1162X/R1162X 9 99 (13) Pl 27 1949del84/DF508 4 105 (20) Pl 28 DF508/DF508 47 103 (8) Pl This study 62111G3T/DF508 28 103 (7) Pl This study 62111G3T/A455E 6 94 (11) Pl/PS This study A455E/DF508 12 77 (18) Pl/PS This study a Or other 'severe` mutations. Login to comment

PMID: 9454574 [PubMed] Wigley WC et al: "Transmembrane domain of cystic fibrosis transmembrane conductance regulator: design, characterization, and secondary structure of synthetic peptides m1-m6."

No. Sentence Comment

261 The critical importance of this intramembrane residue to CFTR structure is highlighted by the CF-causing mutation of proline 205 to serine (54), which prevents proper folding and processing of CFTR (52) and causes a form of cystic fibrosis similar to other misprocessing mutants such as A455E and P574H (55). Login to comment

PMID: 9550360 [PubMed] De Braekeleer M et al: "Complete identification of cystic fibrosis transmembrane conductance regulator mutations in the CF population of Saguenay Lac-Saint-Jean (Quebec, Canada)."

No. Sentence Comment

18 CFTR mutations in Saguenay LacSaint-Jean We previously reported, based on 91 families, that three mutations (AF508,621 +1G+T, and A455E) accounted for 90% of the CF chromosomes while eight mutations represented 93% of the mutations (6, 7). Login to comment
31 There were 11 patients with a AF508/AF508 genotype, two with AF508/621 +l G + T and one with AF508/A455E and N1303K/I148T genotype each. Login to comment
33 Distributon of CFTR mutations in CF patients born in SLSJ Mutations No. CF chromosomes Proportion(%) AF508 120 621tlG-T 51 A455E 17 Y1092X 3 1148T 2 711+1G+T 2 G85E 1 Q890X 1 s489x 1 R117C 1 R1158X 1 60 25.5 8.5 1.5 1 1 0.5 0.5 0.5 0.5 0.5 Table 1 gives the distribution of the mutations found on the C F chromosomes from patients born in the SLSJ region. Login to comment
34 Ninety four percent of the CF chromosomes were accounted for by only three mutations: AF508, 621 +1G+T and A455E. Login to comment
43 Distributionof CFtR genotypes in CF patients born in SLSJ Genotypes No. CF patients AFS08/AF508 AF5@/621+lG-T AF508/A455E 621t 1G+T/A455E 621t 1G+T/621 t 1G-T AF508,N109W AF508/1148T 621t1G+T/711 t1G+T 621t 1G+T/G85E 621t1G+T/YlO92X A455E/R117C 621+1G+TjS489X AF508/Q890X AF508/R1158X 37 30 6 5 2 2 2 1 1 1 1 1 1 45 De Braekeleer et al. identify 100% of the CFTR mutations in the CF population born in SLSJ. Login to comment

PMID: 9374850 [PubMed] McNicholas CM et al: "A functional CFTR-NBF1 is required for ROMK2-CFTR interaction."

No. Sentence Comment

15 Also, oocytes expressing both ROMK2 and CFTR mutants with naturally occurring NBF1 point mutations, CFTR-G551D or CFTR-A455E, display glibenclamide-inhibitable Kϩ currents of only 14 and 25%, respectively. Login to comment
69 The oligonucleotides used for mutagenesis were CFTR-G551D:5Ј GAGTGGAGAT- CAACGAG 3Ј, CFTR-A455E:5Ј GTTGTTGGAGGTTGCTGG 3Ј, CFTR-K370X:5Ј GCAATAAACTAAATACAGGATATCTTAC 3Ј, and CFTR-K593X:5Ј CTGTTAACTGATGGCTAGCAAACTAGG 3Ј. Login to comment
84 To test our hypothesis, we measured the glibenclamide sensitivity of the Kϩ currents (using the experimental protocol described above) when ROMK2 was coexpressed with two engineered CFTR-mutant constructs, CFTR-K593X or CFTR-K370X, or two naturally occurring CFTR-mutant constructs, CFTR-G551D or CFTR-A455E (see Fig. 2). Login to comment
87 In our initial experiments with the mutant CFTR constructs, we coexpressed ROMK2 with either CFTR truncated after NBF1 (CFTR-K593X, Fig. 2) or CFTR truncated before NBF1 (CFTR-K370X, Fig. 2). Login to comment
95 A: two naturally occurring first nucleotide binding folds (NBF1) mutants, CFTR-G551D and CFTR-A455E. Login to comment
96 B: CFTR-K593X, a mutant truncated at residue 593, has an intact NBF1. Login to comment
102 When ROMK2 and CFTR-K370X were coexpressed, the observed Ba2ϩ- sensitive Kϩ currents decreased by only 12.3 Ϯ 3.3% (n ϭ 12) after oocytes were exposed to glibenclamide. Login to comment
104 Next, we coexpressed ROMK2 with naturally occurring CFTR mutations within NBF1 (CFTR-G551D or CFTR-A455E). Login to comment
110 Sensitivity of CFTR Cl- currents to glibenclamide Construct Whole Cell Current, nA %Inhibition By Glibenclamide n P CFTR-WT 560Ϯ150 51.9 9 CFTR-K593X 190Ϯ31 50.1 8 NS CFTR-K370X 183Ϯ85 44.1 5 NS CFTR-G551D 334Ϯ80 49.6 7 NS CFTR-A455E 299Ϯ27 63.2 5 NS Uninjected 26Ϯ10 0 5 0.02 Values are means Ϯ SE; n is no. of experiments. Login to comment
120 Effect of glibenclamide on Ba2ϩ-sensitive currents for ROMK2 coexpressed with CFTR mutants CFTR-K593X and CFTR-G551D. Login to comment
121 Time course showing whole cell currents at Vhold ϭ -60 mV for Xenopus oocytes expressing ROMK2:CFTR-K593X (A) and ROMK2: CFTR-G551D (B) obtained using 2-microelectrode voltage-clamp techniques. Login to comment
128 Average Ba2ϩ-sensitive whole cell currents for each condition are as follows: ROMK2 alone ϭ 11.35 Ϯ 3.3 µA, ROMK2:CFTR-WT ϭ 8.29 Ϯ 0.9 µA, ROMK2:CFTR-G551D ϭ 5.57 Ϯ 0.66 µA, ROMK2:CFTR-K593X ϭ 2.37 Ϯ 0.7 µA, ROMK2: A455E ϭ 6.26 Ϯ 1.39 µA, and ROMK2:K370X ϭ 5.57 Ϯ 0.66 µA. A455E (Fig. 2). Login to comment
129 Coexpressing ROMK2 with CFTR-A455E resulted in Ba2ϩ-sensitive outward currents that were not significantly inhibited by glibenclamide (n ϭ 10) (Fig. 4). Login to comment
131 The data from oocytes coexpressed with ROMK2 and either CFTR-G551D or CFTR-A455E demonstrate that at least two amino acids in NBF1 are necessary for the ROMK2-CFTR interaction. Login to comment
9 Also, oocytes expressing both ROMK2 and CFTR mutants with naturally occurring NBF1 point mutations, CFTRG551D or CFTR-A455E, display glibenclamide-inhibitable K1 currents of only 14 and 25%, respectively. Login to comment
62 The oligonucleotides used for mutagenesis were CFTR-G551D:58 GAGTGGAGAT- CAACGAG 38, CFTR-A455E:58 GTTGTTGGAGGTTGCTGG 38, CFTR-K370X:58 GCAATAAACTAAATACAGGATATCTTAC 38, and CFTR-K593X:58 CTGTTAACTGATGGCTAGCAAACTAGG 38. Login to comment
77 To test our hypothesis, we measured the glibenclamide sensitivity of the K1 currents (using the experimental protocol described above) when ROMK2 was coexpressed with two engineered CFTR-mutant constructs, CFTR-K593X or CFTR-K370X, or two naturally occurring CFTR-mutant constructs, CFTR-G551D or CFTR-A455E (see Fig. 2). Login to comment
123 The data from oocytes coexpressed with ROMK2 and either CFTR-G551D or CFTR-A455E demonstrate that at least two amino acids in NBF1 are necessary for the ROMK2-CFTR interaction. Login to comment

PMID: 9415304 [PubMed] Drittanti L et al: "Cystic fibrosis: gene therapy or preventive gene transfer?"

No. Sentence Comment

13 Although mild mutations like A455E can significantlyference between 'being the cause of` and 'being interactive with` refers to the duration of the functional inter- delay arrival of the PNR, mutant CFTR (including A455E) cannot avoid the lung reaching the PNR nor progressingaction between the elements in play, namely CFTR and CF. Login to comment
22 According to the epidemiological data, the com-A455E mutations) up to a point where further progression of the phenotype is independent of the CFTR mon rate of death for lung disease CF patients is rn = 15% per year; putting the PNR roughly around at least 6-7activity (or the mutation on the Cftr).1-4 Based on our data, which indicate that the CFTR would be noninter- years before death.1 The 6-7-year span of the lung disease covers greater than 50% of the life span (approximatelyactive throughout the course of the disease it causes, we postulate a new model describing the course of CF. Login to comment
31 a mild A455E-like lung CF pathway is the time needed for reaching the PNR. Login to comment
32 Beyond the PNR both kinetics areThe concept of PNR has been derived from epidemiological evidence.1 As its biological nature has not been the same.1,3 Therefore, for a young presymtomatic CF lung, a delay in the PNR would mimic the differencecharacterised, a precise definition of the border between CF disease and lung disease based on clinical data is so far between developing a severe CF phenotype (like ⌬F508) or developing a mild CF phenotype (like A455E). Login to comment
16 Although mild mutations like A455E can significantly ference between 'being the cause of` and 'being interactive with` refers to the duration of the functional inter- delay arrival of the PNR, mutant CFTR (including A455E) cannot avoid the lung reaching the PNR nor progressing action between the elements in play, namely CFTR and CF. Login to comment
25 According to the epidemiological data, the com- A455E mutations) up to a point where further progression of the phenotype is independent of the CFTR mon rate of death for lung disease CF patients is rn = 15% per year; putting the PNR roughly around at least 6-7 activity (or the mutation on the Cftr).1-4 Based on our data, which indicate that the CFTR would be noninter- years before death.1 The 6-7-year span of the lung disease covers greater than 50% of the life span (approximately active throughout the course of the disease it causes, we postulate a new model describing the course of CF. Login to comment
34 a mild A455E-like lung CF pathway is the time needed for reaching the PNR. Login to comment
35 Beyond the PNR both kinetics are The concept of PNR has been derived from epidemiological evidence.1 As its biological nature has not been the same.1,3 Therefore, for a young presymtomatic CF lung, a delay in the PNR would mimic the difference characterised, a precise definition of the border between CF disease and lung disease based on clinical data is so far between developing a severe CF phenotype (like DF508) or developing a mild CF phenotype (like A455E). Login to comment

PMID: 9511935 [PubMed] Bianchet MA et al: "Modeling of nucleotide binding domains of ABC transporter proteins based on a F1-ATPase/recA topology: structural model of the nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator (CFTR)."

No. Sentence Comment

34 Other missense mutations are found in or near the motif GX4GK[T/S], i.e., A455E and G458V. Login to comment
360 The CFTR NBD1 model that results (Fig. 6) gathers the disease causing mutations in three different clusters: (1) mutations affecting the nucleotide binding pocket and the putative general base: A455E, G458V, E504Q AI507 AF508 P574H; (2) mutations in motif C which are probably related to an interaction with region D: S549[R,N,I] G551[S,D], R553Q; and (3) mutations within or near motif B, L558S, A559T, R560T, Y563N and mutations S492F and G480C. Login to comment

PMID: 9511929 [PubMed] Devidas S et al: "CFTR: domains, structure, and function."

No. Sentence Comment

121 For example, two mutations,A455E and G55ID, are associated with milder and more severe forms of CF, respectively. Login to comment
122 When these two mutations are studied in airway cells, both could still conduct Cl- , however, only CFTR bearing the A455E mutation retained the function of regulating ORCC. Login to comment

PMID: 9379167 [PubMed] Tabcharani JA et al: "Halide permeation in wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels."

No. Sentence Comment

21 Mutations in CFTR that cause it to be mislocalized (i.e., ⌬F508) or unresponsive (i.e., G551D) are associated with severe forms of cystic fibrosis, whereas mutations that only partially reduce CFTR conductance (R347P,H, Sheppard et al., 1993; Tabcharani et al., 1993), open probability (R117H, Sheppard et al., 1993; Becq et al., 1994; intracellular loop IV mutants, Seibert et al., 1996), or processing (A455E, Sheppard et al., 1995) are associated with milder symptoms. Login to comment
24 Mutations in CFTR that cause it to be mislocalized (i.e., DF508) or unresponsive (i.e., G551D) are associated with severe forms of cystic fibrosis, whereas mutations that only partially reduce CFTR conductance (R347P,H, Sheppard et al., 1993; Tabcharani et al., 1993), open probability (R117H, Sheppard et al., 1993; Becq et al., 1994; intracellular loop IV mutants, Seibert et al., 1996), or processing (A455E, Sheppard et al., 1995) are associated with milder symptoms. Login to comment

PMID: 9311495 [PubMed] Ho LP et al: "Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis."

No. Sentence Comment

25 Homozygotes for ∆F508 mutation have been found to have a greater incidence of pancreatic insufficiency, worse lung function and higher mortality compared to other genotypes [2, 3] while isolated mutations such as A455E are associated with a mild clinical course [4]. Login to comment
60 Data analysis Patients were divided into two groups, according to genotype: 1) mutations that fail to generate significant apical membrane protein (∆F508/∆F508, ∆F508/ W1282X, ∆F508/Q493X) and 2) mutations where gene product is present in the apical membrane (∆F508/G551D, ∆F508/ A455E, ∆F508/R117H, G551D/G551D) [12]. Login to comment
123 All, however, were pancreatic insufficient and were colonized by Pseudomonas spp. The only two pancreatic sufficient subjects were those who also showed the two highest values for chloride secretion ( genotypes A455E/∆F508 and R117H/∆F508). Login to comment

PMID: 9164776 [PubMed] Gregg RG et al: "Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods."

No. Sentence Comment

152 DNA Analysis of Genotyped CF Patients in the US* n Percent ⌬F508 12701 67.7 G542X 403 2.2 G551D 357 1.9 W1282X 240 1.3 N1303K 223 1.2 R553X 157 0.8 3849 ϩ 10kbC 3 T 102 0.5 621 ϩ 1G 3 T 147 0.8 1717 - 1G 3 A 101 0.5 R117H 101 0.5 R334W 36 0.2 ⌬I507 42 0.2 R347P 37 0.2 R560T 23 0.1 R1162X 44 0.2 2789 ϩ 5G 3 A 25 0.1 A455E 16 0.1 3120 ϩ IG 3 A 14 0.0 S549N 12 0.0 711 ϩ IG 3 T 9 0.0 Other 178 0.9 Unidentified 3814 20.3 Total 18782 99.7† Patient Genotypes Allele 1/Allele 2 n % of Genotype ⌬F508/⌬F508 4573 48.7 ⌬F508/Known 1511 16.1 ⌬F508/Unknown 2044 21.8 Known/unknown 310 3.3 Known/known 223 2.4 Unknown/unknown 730 7.8 Total 9391 100.0 *Data from Cystic Fibrosis Registry, 1995; Annual Report. Login to comment
147 DNA Analysis of Genotyped CF Patients in the US* n Percent DF508 12701 67.7 G542X 403 2.2 G551D 357 1.9 W1282X 240 1.3 N1303K 223 1.2 R553X 157 0.8 3849 1 10kbC 3 T 102 0.5 621 1 1G 3 T 147 0.8 1717 2 1G 3 A 101 0.5 R117H 101 0.5 R334W 36 0.2 DI507 42 0.2 R347P 37 0.2 R560T 23 0.1 R1162X 44 0.2 2789 1 5G 3 A 25 0.1 A455E 16 0.1 3120 1 IG 3 A 14 0.0 S549N 12 0.0 711 1 IG 3 T 9 0.0 Other 178 0.9 Unidentified 3814 20.3 Total 18782 99.7ߤ Patient Genotypes Allele 1/Allele 2 n % of Genotype DF508/DF508 4573 48.7 DF508/Known 1511 16.1 DF508/Unknown 2044 21.8 Known/unknown 310 3.3 Known/known 223 2.4 Unknown/unknown 730 7.8 Total 9391 100.0 *Data from Cystic Fibrosis Registry, 1995; Annual Report. Login to comment

PMID: 9150159 [PubMed] Macek M Jr et al: "Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%."

No. Sentence Comment

39 Mutation Analysis All patients were screened for the AF508 mutation and 15 common Caucasian CF mutations using a reverse dot strip hybridization system (Kawasaki et al. 1993) (R117H, 621+1G--T, R334W, R347P, A455E, A1507, 1717-1G-+A, G542X, S549N, GSS1D, R553X, R560T, 3849+10kbC-+T, W1282X, and N1303K) (Welsh et al. 1995) and a deep intron 11 splice-site mutation, 1811+1.6kbA-+G (Chillon et al. 1995). Login to comment
86 The most common muta- Table 2 Distribution of CF Mutations in African-American and U.S.-Caucasian CF Patients African-American U.S. Caucasiana Mutation (n= 148) % (n = 8,714) % Caucasian mutations: AF508 71 48 5,769 66.2 R117H 0 0 47 .5 621+1 G--T 0 0 68 .8 R334W 1 .7 7 .1 R347P 0 0 24 .3 A455E 0 0 5 .1 AI507 1 .7 10 .1 1717-1 G-IA 1 .7 39 .5 G542X 1 .7 204 2.3 S549N 1 .7 4 .1 GS51D 1 .7 173 2.0 R553X (Caucasian)b 0 0 87 1.0 R560T 0 0 16 .2 3849+10kb C-T 0 0 51 .6 W1282X 0 0 235 2.7 N1303K 0 0 116 1.3 Subtotal 77 52 6,855 78.7 African-American mutations: 405+3 A-C 2 1.4 ... ... 444delA 1 .7 ... ... G480C 2 1.4 ... ... R553X (African)b 3 2.0 ... ... A559T 3 2.0 ... ... 2307insA 3 2.0 ... ... 3120+1 GC-A 18 12.2 ... ... S1255X 2 1.4 ... ... Subtotal 34 23 ... ... Total 111 75.0 6,855 78.7 NOTE.-Percentages are rounded. Login to comment
40 Mutation Analysis All patients were screened for the AF508 mutation and 15 common Caucasian CF mutations using a reverse dot strip hybridization system (Kawasaki et al. 1993) (R117H, 621+1G--T, R334W, R347P, A455E, A1507, 1717-1G-+A, G542X, S549N, GSS1D, R553X, R560T, 3849+10kbC-+T, W1282X, and N1303K) (Welsh et al. 1995) and a deep intron 11 splice-site mutation, 1811+1.6kbA-+G (Chillon et al. 1995). Login to comment
87 The most common muta- Table 2 Distribution of CF Mutations in African-American and U.S.-Caucasian CF Patients African-American U.S. Caucasiana Mutation (n= 148) % (n = 8,714) % Caucasian mutations: AF508 71 48 5,769 66.2 R117H 0 0 47 .5 621+1 G--T 0 0 68 .8 R334W 1 .7 7 .1 R347P 0 0 24 .3 A455E 0 0 5 .1 AI507 1 .7 10 .1 1717-1 G-IA 1 .7 39 .5 G542X 1 .7 204 2.3 S549N 1 .7 4 .1 GS51D 1 .7 173 2.0 R553X (Caucasian)b 0 0 87 1.0 R560T 0 0 16 .2 3849+10kb C-T 0 0 51 .6 W1282X 0 0 235 2.7 N1303K 0 0 116 1.3 Subtotal 77 52 6,855 78.7 African-American mutations: 405+3 A-C 2 1.4 ... ... 444delA 1 .7 ... ... G480C 2 1.4 ... ... R553X (African)b 3 2.0 ... ... A559T 3 2.0 ... ... 2307insA 3 2.0 ... ... 3120+1 GC-A 18 12.2 ... ... S1255X 2 1.4 ... ... Subtotal 34 23 ... ... Total 111 75.0 6,855 78.7 NOTE.-Percentages are rounded. Login to comment

PMID: 9154877 [PubMed] Walker LC et al: "Relationship between airway ion transport and a mild pulmonary disease mutation in CFTR."

No. Sentence Comment

1 We studied airway bioelectric properties in five CF patients with the rare A455E mutation that is associated with mild pulmonary disease. Login to comment
5 Based on our findings in a naturally occurring group of CF patients with an improved pulmonary prognosis (A455E), one can argue that marked clinical benefit might be possible without any improvement whatsoever in airway bioelectric phenotype. Login to comment
6 Moreover, if genetic modifiers exist that influence the severity of a particular CFTR mutation (e.g., A455E), these may be independent of human airway Cl secretion in vivo, since we detected minimal Cl- -secretory responses in patients with A455E. Login to comment
45 Expression of CFTR in COS-7 (Simian Kidney) Cells Expression of wild type, AF508 or A445E CFTR under the regulatory control of the 17 promoter was studied with the pTM1 vector (gift of Dr. B. Moss, of the National Institutes of Health; the A455E construct in this vector backbone was a generous gift of Dr. M. Welsh of the University of Iowa). Login to comment
59 RESULTS Table 1 summarizes clinical features of the A455E, G542X, and R553X CF patients we studied. Login to comment
62 Taken together, there had been a total of 10 hospital admissions for intravenous antibiotic therapy among the A455E patients, and more than 36 admissions among the patients with truncation mutations. Login to comment
67 Decisions regard- -10 26t5 mV -39*9 mVtt -57±5 mVtt -43*9 mVtt Control G542X or R553X A544E AF508 B 50 40 • C A PD 30 • (mV) • 20 • •• 10 ' • • o - t----------------------------- aj J0 mVtt -27±8 mVtt Control G542X or R553X A455E AF508 C -40 -30 1686 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 155 1997 A -60 -50 • t 1 ' PD max -40 I (mV) • • • -30 • • s-20 to mV L - - i--- --- - -- -------loses A Amilo,id Amilonde Amiloride Low CI' Low Cl* fenol lomV L l0 Sea --------------^--------- --------t- - --- -- - --------- l0 mV L ------^--- --------Y- -^ t t lOmV L 10Sa. Login to comment
71 Genotypes of the patients shown include B:A455E/621 + 1 G-*T; C:AF508/A455E; and D:R553X/G542X. Login to comment
74 Figure 1B and C show tracings from compound heterozygotes for the A455E mutation. Login to comment
77 The remainder of patients with the A455E mutation exhibited no response to low Cl- /isoproterenol, as in the tracing in Figure I.C. Figure 1D shows a tracing from a patient homozygous for truncation mutations within CFTR (G542X/R553X). Login to comment
80 Figure 2 shows a summary of the data from patients and healthy controls in the study, and describes the baseline PD during perfusion with lactated Ringer's solution (Figure 2A), -20 APD (mv) • -10 tl • 0•------'------------------s---------------------------------- --- 10 12t7 mV -2:4 rVtt -4t8 mVtt -5)mVtt Control G542X or R553X A455E AF508 Figure 2. Login to comment
89 In B, both A455E and AF508 differed from the truncation mutation group (p < 0.01). Login to comment
92 When data from each experimental group are taken together, neither A455E patients nor those with truncation mutations showed evidence of either a Cl- -secretory response (Figure 2C) or a suggestion of normalization of this aspect of the PD measurement. Login to comment
93 In the A455E patients, the maximal PD during perfusion with lactated Ringer's solution and the change after amiloride were well within the range anticipated for the general CF population (Figure 2A and B; [6-21]). Login to comment
94 In the patients with CFTR truncations G542X or R553X, the magnitude of the amiloride-sensitive PD (Figure 2B) was less than in A455E or AF508 patients, although these measurements were still highly useful in discriminating all CF patient groups from individuals without CF (p < 0.01). Login to comment
98 On the basis of these in vivo experiments, we were interested in studying the in vitro activity of CFTR containing the A455E mutation. Login to comment
99 During in vitro overexpression in heterologous cells, the A455E mutation has been reported to exhibit partial Cl- -channel activity (7). Login to comment
101 The results indicate that cAMP-dependent increases in halide permeability occur after A455E CFTR overexpression in vitro, and are intermediate between halide permeability with wild-type and AF508 CFTR. Login to comment
102 DISCUSSION The A455E mutation in CFTR has been associated with improved FEV1 and FVC, a reduced incidence of pulmonary colonization by Pseudomonas aeruginosa, better exocrine pancreatic function, residual Cl- -channel activity in vitro, and improved overall prognosis in CF (2-7). Login to comment
106 The incidence of A455E in both populations is believed to be based on a genetic founder effect. Login to comment
109 However, our results suggest that whether it is the A455E mutation itself or (as yet undetermined) interactions with other genes that lead to mild lung disease, the mitigating factor is independent of large improvements in either transepithelial Cl- or Na+ transport, since no such improvements were observed in our experiments. Login to comment
111 It.ie not known whether the airway bioelectric measurement is sufficiently sensitive to identify a lower limit of gene transfer necessary to provide benefit in this setting, --A-- A455E (11/53) 0 eF508 (0/27) CFTR (42/42) S S S S S 0 0 S SCl C) er U) 10 h CD 0) SECONDS Figure 3. Login to comment
112 Functional assay of cAMP-mediated halide permeability in COS-7 cells transiently expressing wild-type (open circles), A455E (open triangles), or AF508 CFTR (filled diamonds). Login to comment
117 Approximately 20% of A455E cells (11 of 53) had a detectable cAMP response comparable with that of the wild-type CFTR. Login to comment
118 Each curve is the mean ± SEM of responding (wild-type CFTR or A455E) or total (ÁF508) cells. Login to comment
119 A455E responses differed from those of AF508 (p < 0.001). Login to comment
124 We also studied the A455E mutation in a recombinant overexpression system used to analyze the function of CFTR mutations (24-27). Login to comment
125 The data presented in Figure 3 indicate that A455E retains residual activity when studied in vitro. Login to comment
127 Together with our in vivo experiments, this result suggests that A455E is active following overexpression, but that the activity in vivo is not detectable by the nasal PD assay. Login to comment
129 First, the nasal PD, the best available method for studying the CF bioelectric phenotype in vivo, may not be sufficiently sensitive to detect clinically important improvements in Cl- secretion in a small number of CF patients with an improved prognosis (i.e, five individuals with the A455E mutation). Login to comment
131 Alternatively, since the levels of A455E J m m m A LL w y w V z 51 dequench cAMP AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 155 1997 mRNA or protein in vivo are not known, it is possible that previous in vitro overexpression studies of A455E (and the results shown in Figure 3) reflect a phenomenon that does not predict activity of the mutation in vivo. Login to comment
132 For example, it is possible that detectable A455E C1 - -channel activity in isolated cells or membrane patches depends on a very high level of protein expression that is absent in vivo. Login to comment
133 Because PD measurements detect Cl- secretion across polarized epithelium, studies of A455E in nonpolarized cells grown on plastic might have quite different results from the in vivo situation. Login to comment
44 Expression of CFTR in COS-7 (Simian Kidney) Cells Expression of wild type, AF508 or A445E CFTR under the regulatory control of the 17 promoter was studied with the pTM1 vector (gift of Dr. B. Moss, of the National Institutes of Health; the A455E construct in this vector backbone was a generous gift of Dr. M. Welsh of the University of Iowa). Login to comment
58 RESULTS Table 1 summarizes clinical features of the A455E, G542X, and R553X CF patients we studied. Login to comment
61 Taken together, there had been a total of 10 hospital admissions for intravenous antibiotic therapy among the A455E patients, and more than 36 admissions among the patients with truncation mutations. Login to comment
66 Decisions regard- -10 26t5 mV -39*9 mVtt -57&#b1;5 mVtt -43*9 mVtt Control G542X or R553X A544E AF508 B 50 40 ߦ C A PD 30 ߦ (mV) ߦ 20 ߦ ߦ ߦ 10 ' ߦ ߦ o - t---------------------------- - aj J0 mVtt -27&#b1;8 mVtt Control G542X or R553X A455E AF508 C -40 -30 1686 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 155 1997 A -60 -50 ߦ t 1 ' PD max -40 I (mV) ߦ ߦ ߦ -30 ߦ ߦ s -20 to mV L - - i--- --- - -- -------loses A Amilo,id Amilonde Amiloride Low CI' Low Cl* fenol lomV L l0 Sea --------------^--------- --------t- - --- -- - --------- l0 mV L ------^--- --------Y- -^ t t lOmV L 10Sa. Login to comment
70 Genotypes of the patients shown include B:A455E/621 + 1 G-*T; C:AF508/A455E; and D:R553X/G542X. Login to comment
73 Figure 1B and C show tracings from compound heterozygotes for the A455E mutation. Login to comment
76 The remainder of patients with the A455E mutation exhibited no response to low Cl- /isoproterenol, as in the tracing in Figure I.C. Figure 1D shows a tracing from a patient homozygous for truncation mutations within CFTR (G542X/R553X). Login to comment
79 Figure 2 shows a summary of the data from patients and healthy controls in the study, and describes the baseline PD during perfusion with lactated Ringer's solution (Figure 2A), -20 APD (mv) ߦ -10 tl ߦ 0ߦ------' ------------------s---------------------------------- --- 10 12t7 mV -2:4 rVtt -4t8 mVtt -5)mVtt Control G542X or R553X A455E AF508 Figure 2. Login to comment
88 In B, both A455E and AF508 differed from the truncation mutation group (p < 0.01). Login to comment
91 When data from each experimental group are taken together, neither A455E patients nor those with truncation mutations showed evidence of either a Cl- -secretory response (Figure 2C) or a suggestion of normalization of this aspect of the PD measurement. Login to comment
97 On the basis of these in vivo experiments, we were interested in studying the in vitro activity of CFTR containing the A455E mutation. Login to comment
100 The results indicate that cAMP-dependent increases in halide permeability occur after A455E CFTR overexpression in vitro, and are intermediate between halide permeability with wild-type and AF508 CFTR. Login to comment
104 The incidence of A455E in both populations is believed to be based on a genetic founder effect. Login to comment
107 However, our results suggest that whether it is the A455E mutation itself or (as yet undetermined) interactions with other genes that lead to mild lung disease, the mitigating factor is independent of large improvements in either transepithelial Cl- or Na+ transport, since no such improvements were observed in our experiments. Login to comment
110 Functional assay of cAMP-mediated halide permeability in COS-7 cells transiently expressing wild-type (open circles), A455E (open triangles), or AF508 CFTR (filled diamonds). Login to comment
115 Approximately 20% of A455E cells (11 of 53) had a detectable cAMP response comparable with that of the wild-type CFTR. Login to comment
116 Each curve is the mean &#b1; SEM of responding (wild-type CFTR or A455E) or total (&#c1;F508) cells. Login to comment
122 We also studied the A455E mutation in a recombinant overexpression system used to analyze the function of CFTR mutations (24-27). Login to comment
123 The data presented in Figure 3 indicate that A455E retains residual activity when studied in vitro. Login to comment
130 For example, it is possible that detectable A455E C1 - -channel activity in isolated cells or membrane patches depends on a very high level of protein expression that is absent in vivo. Login to comment

PMID: 9098486 [PubMed] Villalobos-Torres C et al: "Analysis of 16 cystic fibrosis mutations in Mexican patients."

No. Sentence Comment

60 Mutation Frequency Data and Geographic Distribution of the Mutations Found in 80 Chromosomes From Mexican CF Patients Mutation Northeast n ‫ס‬ 54 Central n ‫ס‬ 16 Western n ‫ס‬ 10 Total n ‫ס‬ 80 CFGAC [1994] (%)n (%) n (%) n (%) n (%) ⌬F508 27 (50) 2 (12.5) 7 (70) 36 (45) 66 G542X 2 (3.7) 2 (12.5) 0 4 (5) 2.4 3849 + 10 kb C→T 1 (1.9) 0 1 (10) 2 (2.5) 0.2 N1303K 0 1 (6.25) 0 1 (1.25) 1.3 S549N 0 1 (6.25) 0 1 (1.25) 0.1 621 + 1 G→T 0 0 1 (10) 1 (1.25) 0.7 Othera 24 (44.4) 10 (62.5) 1 (10) 35 (43.7) Detected 30 (55.6) 6 (37.5) 9 (90) 45 (56.3) a Different from W1282X, R117H, R334W, R347P, A455E, ⌬I507, 1717 - 1 G→T, G551D, R553X, and R560T. Login to comment

PMID: 9135734 [PubMed] Porteous DJ et al: "Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis."

No. Sentence Comment

32 Table 1 Anthropometric data Group Patient Gender Age Genotype FEV1 No (% predicted) Placebo 03 Female 33 ⌬F508/R117H 57 06 Male 27 ⌬F508/⌬F508 55 08 Female 29 ⌬F508/A455E 97 11 Female 42 ⌬F508/Q493X 24 15 Male 30 ⌬F508/R560T 20 16 Female 20 ⌬F508/⌬F508 70 18 Female 27 ⌬F508/⌬F508 21 21 Female 20 ⌬F508/⌬F508 20 Mean (s.d.) 6F, 2M 28.5 (7.1) 51.9 (28.1) Treated 01 Male 31 ⌬F508/G551D 45 05 Female 30 ⌬F508/⌬F508 91 09 Male 32 G551D/G551D 37 10 Female 29 ⌬F508/⌬F508 63 13 Male 16 ⌬F508/⌬F508 55 14 Female 37 ⌬F508/G551D 66 19 Male 23 ⌬F508/W1282X 37 23 Female 21 ⌬F508/G551D 53 Mean (s.d.) 4F, 4M 27.4 (6.8) 55.9 (17.8) and illustrative results shown in Figure 3. Login to comment

PMID: 9401006 [PubMed] Shrimpton AE et al: "Cystic fibrosis mutation frequencies in upstate New York."

No. Sentence Comment

84 % Comment 3 G85E 1 1 0.5 4 R117H 1 1 0.5 i4 621 + 1,G>T 1 2 3 1.5 5 711 + 1,G>T 1 1 0.5 6b N287Y 1 1 0.5 Novel 7 1154insTC 2 2 1.0 8 1259insA 1 1 0.5 Novel 9 A455E 1 1 0.5 10 Delta F508 109 39 148 74.0 10 1609delCA 1 1 0.5 Spanish i10 1717-1,G>A 3 3 1.5 11 G542X 2 1 3 1.5 11 G551D 3 3 1.5 11 R553X 4 4 2.0 i12 1898+1,G>A 2 2 1.0 13 2143delT 1 1 0.5 13 2184delA+G>A 1 1 0.5 i14 2789+5,G>A 2 2 1.0 17b R1070P 1 1 0.5 Novel 17b Y1092X(C>A) 2 2 1.0 French Canadian (Rozen et al., 1992) 17b CF?20kbdel 14b-18 1 1 0.5 Novel (Shrimpton and Borowitz, 1997) i19 3849+10kb,C>T 1 1 0.5 20 W1282X 2 2 0.5 Ashkenazi 21 N1303K 3 3 6 3.0 Unknown 4/144 4/56 8/200 4.0 AL. 75 and 81 mMol/L. Login to comment

PMID: 9375855 [PubMed] Casals T et al: "Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients."

No. Sentence Comment

56 The current clinical data for missense mutations derived from a relatively large number of cases are limited to a few mutations: N1303K (Osborne et al., 1992; CF genotype-phenotype Consortium 1993), R117H (CF genotype-phenotype Consortium 1993), P205S (Chillón et al., 1993), A455E (Gan et al., 1995), L206W (Desgeorges et al., 1995), R334W (Estivill et al., 1995), and G85E (Vázquez et al., 1996). Login to comment

PMID: 9067754 [PubMed] Macek M Jr et al: "Sensitivity of the denaturing gradient gel electrophoresis technique in detection of known mutations and novel Asian mutations in the CFTR gene."

No. Sentence Comment

42 621 + 1 GÃT, R334W, R347P, A455E, aI507, aF508, 1717-1 GÃA, G542X, S549N, G551D, R553X, R560T, 3849 + 10kb CÃT, W1282X, and N1303K) was performed using the rapid multiplex reverse dot hybridization system, under conditions provided by Roche Molecular Systems (Alameda, CA) (Kawasaki et al., 1993; Welsh et al., 1995). Login to comment

PMID: 8947061 [PubMed] Hubert D et al: "Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients."

No. Sentence Comment

22 Concerning the relationship between the severity of pulmonary involvement and other mutations than ∆F508, a mild pulmonary disease was described in two sisters homozygous for the G551S mutation [13], and in compound heterozygotes for the missense mutation A455E, a mutation commonly found in The Netherlands [14]. Login to comment
112 In the studies by GAN et al. [14], and STRONG et al. [13] patients with the A455E mutation or with the G551S mutation, respectively, who would be classified as Group 3 in the present study, had mild pulmonary disease. Login to comment

PMID: 8702904 [PubMed] Cotten JF et al: "Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

222 For example, H1085R is misprocessed like ⌬F508, yet it is reported to occur in a patient with a pancreatic sufficient phenotype. Login to comment
223 Conversely, our data with the mutants R1066L, R1066H, and A1067T are similar to that obtained with the "mild" mutants A455E and P574H (10) in that they retained partial processing and function. Login to comment

PMID: 8863168 [PubMed] Parad RB et al: "Heterogeneity of phenotype in two cystic fibrosis patients homozygous for the CFTR exon 11 mutation G551D."

No. Sentence Comment

59 Consistent pulmo- boplastin nary phenotype has only been suggested with were nor- two mutations, RI 17H and A455E.9 10 CF, and G551D has been characterised as a class III mutation8 through its presumed impact on ATP binding." Login to comment

PMID: 8869353 [PubMed] Alton EW et al: "A mild variant of cystic fibrosis."

No. Sentence Comment

80 Novel findings of the paper by Gan et al The key finding of the paper by Gan et all is the identification of a mutation, A455E, that does appear to correlate with better lung prognosis. Login to comment
82 Lung function was significantly higher in age and sex matched patients than in AF508 homozygotes, fewer patients were colonised with Pseudomonas, and disease was diagnosed at a later age in the subjects with A455E mutation. Login to comment
92 Secondly, from a mechanistic point of view it will be important to understand why the A455E mutation differs from others in predicting a favourable outcome. Login to comment
95 One final consideration relates to the level of chloride secretion present in patients with the A455E mutation, which has been shown to allow residual secretion of chloride. Login to comment
100 A455E may produce a small increase in function above a critical level, resulting, in turn, in a disproportionately large increase in function sufficient to influence lung disease. Login to comment
101 Finally, it is worth noting that, given the relative rarity of some mutations, A455E may not turn out to be the only mutation associated with an improved respiratory prognosis. Login to comment

PMID: 8659542 [PubMed] Miller PW et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis."

No. Sentence Comment

63 DNA samples from ABPA patients were screened for nine additional mutations associated with pancreatic sufficient and atypical CF: R117H (ASO), R347P (NcoI digest) and R347H (HhaI digest), R334W (MspI digest), A455E (ASO and BamHI digest), G551S (ASO) (Strong et al. 1991), 2789+5G-*A (ASO), D1152H (ASO) (Tsui 1992), and 3849+10kbC-*T (ASO and HphI digest) (Highsmith et al. 1994). Login to comment

PMID: 8663008 [PubMed] Sheppard DN et al: "Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function."

No. Sentence Comment

192 In this regard they are similar to the CF mutations A455E and P574H that disrupt processing but generate channels that retain significant activity (23). Login to comment
217 The mechanism of dysfunction of P205S resembles that of the nucleotide-binding domain 1 pancreatic sufficiency mutants A455E and P574H, which are misprocessed (23). Login to comment
198 In this regard they are similar to the CF mutations A455E and P574H that disrupt processing but generate channels that retain significant activity (23). Login to comment
225 The mechanism of dysfunction of P205S resembles that of the nucleotide-binding domain 1 pancreatic sufficiency mutants A455E and P574H, which are misprocessed (23). Login to comment

PMID: 8617131 [PubMed] McGill JM et al: "Survey of cystic fibrosis transmembrane conductance regulator genotypes in primary sclerosing cholangitis."

No. Sentence Comment

33 In total, 32 mutations were evaluated, which represent 90% of the most common mutations (t4): AF508 G542X G551D W1282X 3905insT NI303K 3849+ 10kbC--~T R553X 621+ IG--*T 1717- IG--,A lt)78delT 2789+5G---~A 3849+4A--~G 711+ IG---oT R1162X 1898+IG----~A R117H 3659delC G85E 2184delA A1507 R347P Y1092X R560T A455E R334W Y122X S549R(T---~G) Q493X V520F $549N R347H Patient Selection. Login to comment

PMID: 8844213 [PubMed] Morral N et al: "Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers."

No. Sentence Comment

106 (1992) Dork et al. (1994a) Malone et al. (personal communication) Claustreset al. (1992) Ferec et al. (1992) Fanen et al. (1992) lvaschenko et al. (1991) T. Dork (personal communication) Dean et al. (1990) Dork et al. (1994a) Ferec et al. (1992) Bozon et al. (1994) Costes et al. (personal communication) Fanen et al. (1992) Audrezet et al. (personal communication) Zielenski et al. (1991a) Zielenski et al. (1991a) Granell et al. (1992) Highsmith et al. (1990) Mercier et al. (1993b) Vidaud et al. (1990) Fanen et al. (1992) Fanen et al. (1992) Dork et al. (1994b) (continued) HAPLOTYPESFOR 94 CF MUTATIONS TABLE2. CFTR HaplotvpesforDiallelic and Multiallelic DNA Markers for 94 CF Mutations"(Continued) ~~ ~ J44-GAIT- 8CA-17BTA- No. of TSU-TUB20 17BCA Mutation chromosomes % Normal Laboratory Reference 1-6-1-2 (9.1%) 1-6-2-2 (8.9%) 1-7-1-2 (3.4%) 1-7-2-2 (2.6%) 2-7-1-1 (1.2%) 2-7-2-2 (0.7%) 17-7-16 16-7-18 16-7-17 15-7-17 24-31-13 23-52-13 23-34-13 23-33-14 23-33-13 23-32-13 23-31-13 23-30-13 23-21-19 23-18-13 22-35-13 22-31-13 22-30-13 21-31-13 19-33-13 18-45-13 18-37-13 18-35-13 17-57-11 17-55-13 17-55-11 17-54-11 17-53-11 17-52-11 17-51-11 17-33-13 16-46-13 16-45-13 16-44-13 16-42-13 16-35-13 16-30-13 16-30-13 16-7-17 16-21-19 L107% L1077P 24ldelAT L719X A1507 3849+10kbC-T 2184insA 2991de132 G551D 1154insTC V520F R560T 4114ATA+lT 3667de14 435insA Q414X C225R Q39X N1303K R1162X H199Y G542X G542X w1204x R347H G542X AF50gb N1303K 2143delT 3849f 10kbC-T N1303K 681delC R347H A455E N1303K A120T 621+1 h T 574delA 1221delCT F311L R560K R553X R533X R553X Q552X R553X Q552X R116W R553X 1898+5 h T 3272-26A-G 1717-1hA 1342-2A-C A1507 2869insG 2869insG E92X 4374+1 h T 2183AA-G R117H 1609delCA I336K W1063X 1 1 1 1 6 1 3 1 1 22 17 1 1 1 1 1 1 1 1 1 1 1 1 1 17 1 1 4 157 7 1 2 2 1 1 2 2 1 9 1 1 1 1 1 1 6 1 1 1 2 1 3 2 1 3 1 1 1 4 2 4 1 1 - - 10.33 1.45 - - 0.48 1.45 - 0.24 1.45 0.24 - - - - 0.24 0.48 - - - - - - 0.49 0.48 - 0.24 0.24 0.24 - - - - - 0.72 0.24 0.72 - t h fP h b.fb,fP h b,fp.t t h b.fb.fp,h,t b.fb.fp,h,t t t t h b h h fP h fP fb b fP b.fb,fP,h.t fP fb b,fP,t b.fb,fp,h,t b.fb,h h h h,t t fb t b b b.fb.t fP fb fb tb h fP h h t t b h t h b b h h b,fb,h fP.h b h fP fP Bozon et al. (1994) Fanen et al. (1992) Dork et al. (1994a) Kerem et al. (1990) Dork et al. (1994~) Cutting et al. (1990) Kerem et al. (1990) lannuui et d. Login to comment

PMID: 8829658 [PubMed] Cronin MT et al: "Cystic fibrosis mutation detection by hybridization to light-generated DNA probe arrays."

No. Sentence Comment

238 Cystic Fibrosis Mutation-Specific DNA Probe Array" Mutation Exon and column Tested Subarrayhow G85E R117H I148T 621 -+ l(G+T) 711 + 1(G+T) R334W R347H R347P 1078 delT A455E G480C Q493X A1507 F508C AF508 V520F G542X S549R(T-+ G) G551D Q552X R553X A559T R560T 1898 + l(G-,A) 2184 del A 2789 + 5(G+ A) R1066C L1077P Y1092X R1162X 3659 del C 1717-1(& A) 3272 - 26(A+ G) 3 4 4 in 4 in 5 7 7 7 7 9 10 10 10 10 10 10 in 10 11 11 11 11 11 11 11 in 12 13 in 14b in 17a 17b 17b 17b 19 19 * * * * * * * * * * * * * * * * * * * * * * * * * * * * 3849 + lOkb C-, T in 19 9,3 W1282X 20 994 3905insT 20 10.1 * N1303K 21 10,2 * * * "Row and column locations for each of the mutation specific,40 probe sets included in the specialized probe array design. Login to comment

PMID: 9156582 [PubMed] Gray MA et al: "Chloride channels and cystic fibrosis of the pancreas."

No. Sentence Comment

117 The second group involves residues within NBD1 (A455E and P574H) which are located close to the walker A (residues 458-464) and B (residues 568-572) motifs, crucial for ATP binding. Login to comment
118 The second group involves residues within NBD1 (A455E and P574H) which are located close to the walker A (residues 458-464) and B (residues 568-572) motifs, crucial for ATP binding. Login to comment

PMID: 8553305 [PubMed] Gan KH et al: "Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years."

No. Sentence Comment

41 DNA was analysed for the following mutations: E60X, R117H, A455E, AI507, AF508, G542X, S549N, G550X, G551D, R553X, R560T, R1162X, S1251N, W1282X, N1303K, 621 + 1G-+T, 1717-1G--+A. These mutations represent 80% ofthe expected cystic fibrosis mutations in The Netherlands. Login to comment
69 The A455E mutation was relatively frequent in the LD group. Login to comment
98 Most of those diagnosed at 16 years or older were pancreatic sufficient, which is closely related to the type of CFTR mutation.2829 The A455E mutation was frequently found among this group of patients and preliminary studies indicate that this mutation, known to be related to pancreatic sufficiency,29 may be associated with mild pulmonary disease.30 It seems that other CFTR mutations (some ofwhich are still unidentified) in patients diagnosed late are associated with pancreatic sufficiency and also with mild pulmonary disease. Login to comment

PMID: 7472820 [PubMed] Wilschanski M et al: "Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations."

No. Sentence Comment

13 Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment
43 Defined mutations (each mutation cited in references 8, 23, and 24; numerals in parentheses indicate number of patients): Nonsense mutations-----class I: Frameshift mutations---class I: Splice site mutations-class I: Missense mutations---class HI: Missense mutations---class IV: Partially defective processing---class V: Alternative spficing-----classV: R1162X (3), Y1092X (3), G542X (21), Q552X (2), Q493X (2), w1282x (2), E1104X (1), R553X (6), E585X (l), (all PI) 3659delC (5), 2184delA (4), 4010de14 (1), 556delA (1), 3002delG (1) 3905insT (1), 4016insT (3), 1154insTC (l), 441delA (1), 2184insA (2), 1078delT (1), 4326delTC (3) (all PI) I717-1G--~A (4), 621+lG--*T (10), 711+IG--~T (3), 875+1G-+C (2), 3120+IG-~A (1) (18 PI, 2 PS) G551D (25), N1303K (7), R560T (8), I148T (1), G85E (3), A559T (1), L1077P (2), T1234V (1), (47 PI, 1 PS) R117H (10), R347H (3), R347P (1), D614G (1), S1251N (2), (all PS) P574H (2), A455E (2), (all PS) 3272-26A-+G (4), 3849+10KbC---~T (2), 3120G-+A (1), (all PS) analysis, we further grouped the patients according to the molecular consequences conferred by the CFTR alleles. Login to comment
107 Electrophysiologic studies on the mild mutations A455E and P574H revealed that single-channel conductance was not different from the normal CFFR channel but that less protein reached the membrane. Login to comment
12 Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment

PMID: 7551394 [PubMed] Friedman KJ et al: "Screening Young syndrome patients for CFTR mutations."

No. Sentence Comment

78 Of the 13 Young syndrome patients, we identified one (Patient 5) who was het- CBAVD Dl152H D1270N G576A* R75Q* P67L Rl17H 3849 + 10 KB C > T G551S Rl17H Pancreatic Sufficient, Moderate Pulmonary Symptoms, Normal Sweat Chloride Concentrations Pancreatic Sufficient, Moderate Pulmonary Symptoms R347P 2789 + 5 G > A R334W G85E R347H R347L Rl17H G91R A455E S945L Y563N Q1291H R297Q R352Q L1065P 3850-3 T > G F1286S 3849 + 10 KB C > T TABLE 1 CFTR MUTATION SCREENING PANEL Severe M508 G551D R553X N1303K W1282X G542X 1717-1 G > A ~1507 R560T 3659deiC 621 + 1 G > T S549N TABLE 2 CLINICAL FEATURES OF YOUNG SYNDROME PATIENTS Patient Age Sweat CI- FEV, Paranasal Sputum No. Login to comment

PMID: 7542778 [PubMed] Fulmer SB et al: "Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents."

No. Sentence Comment

4 Both G551D, a mutation that causes severe lung disease, and A455E, a mutation associated with mild lung disease, altered but did not abolish CFTR's function as a chloride channel in Xenopus oocytes. Login to comment
5 Airway epithelial cells transfected with CFTR bearing either A455E or G551D had levels of chloride conductance significantly greater than those of mock-transfected and lower than those of wild-type CFTR-transfected cells, as measured by chloride efflux. Login to comment
7 While CFTrR bearing either mutation could function as a chloride channel, only CFTR bearing A455E retained the function of regulating the ORCC. Login to comment
27 To determine whether disease-associated mutations affect the regulatory function of CFTR, the functional consequences of two mutations, A455E and G551D, were studied. Login to comment
29 When G551D/ AF508 compound heterozygotes were compared with sex- and age-matched AF508 homozygotes, there was no difference in severity of pancreatic or pulmonary disease (15). Login to comment
30 However, comparison of A455E/AF508 compound heterozygotes with AF508 homozygotes revealed significantly better lung function in the heterozygotes, as measured by mean yearly decline in the volume of air forcibly expired in 1 s [forced expiratory volume in 1 s (FEV1); P < 0.0005] (16, 17). Login to comment
31 Since the ORCC appears to be regulated by CFTR in respiratory epithelium, we studied the function of CFTR bearing either A455E or G551D in a Abbreviations: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; ORCC, outwardly rectifying chloride channel; CPT-cAMP, 8-(4-chlorophenylthio)-cAMP; DIDS, 4,4'-diisothiocyanostil- bene-2,2'-disulfonic acid; IBMX, 3-isobutyl-1-methylxanthine; RSV, Rous sarcoma virus. Login to comment
33 Our data suggest that CFTR bearing A455E can function as a cAMP-regulated chloride channel and also maintains its capacity to regulate the ORCC. Login to comment
37 The A455E mutation was created using the oligonucleotide 5'- GTTGTTGGAGGTTGCTGG-3'. Login to comment
46 The mutations, A455E and G551D, were created in pBQ4.7 (a generous gift from J. Rommens and L.-C. Tsui; The Hospital for Sick Children, Toronto) then shuttled to the pAvS6.CFTR or pRSV-CFTR by using Kpn2I and Hpa I (BRL) restriction sites common to all vectors. Login to comment
69 As seen in Fig. 1, oocytes injected with wild-type, G551D-, or A455E-CFTR generated cAMP-stimulated Cl- currents significantly greater than basal level. Login to comment
72 The currents in A455E-CFTR-injected oocytes were about 67% of wild-type, suggesting that A455E-CFTR forms a cAMP-activated chloride channel in Xenopus oocytes. Login to comment
77 |==I Control ~~ Fornkon +IBMX * Control Wild-type G551D A455E FIG. 1. Bar graph summary of Cl- currents (Icl) measured at a clamped voltage of -90 mV before and after stimulation with forskolin (10 ,uM) and IBMX (1 mM) for Xenopus oocytes injected with water (Control; n = 9), wild-type CFTR cRNA (n = 16), G551D-CFTR cRNA (n = 6), or A455E-CFTR cRNA (n = 6). Login to comment
86 IB3-1 cells were transfected with the RSV vector containing wild-type CFTR, G551D-CFTR, or A455E-CFTR. Login to comment
92 IB3-1 cells g+ DIDS were transiently transfected with + Glyb wild-type CFTR (A), G551D-CFTR (B), or A455E-CFTR (C). Login to comment
97 Fifteen seconds after addition of CPT-cAMP, efflux rates from cells transfected with wild-type CFTR (41.7% ± 6.0% of Cl- lost per min; n = 12) or G551D-CFTR (40.8% ± 4.5%; n = 6) were significantly greater (P < 0.05) than that of mock-transfected cells (28.9% ± 4.4%; n = 12). Login to comment
98 Thirty seconds after CPT-cAMP addition, efflux rates from cells transfected with wild-type CFTR (47.8% ± 12.3%; n = 12) and A455E-CFTR (38.1% ± 6.5%; n = 6) were significantly greater (P < 0.05) than that of mock-transfected cells (26.4% ± 5.5%; n = 12). Login to comment
99 These results indicate that both A455E-CFTR and G551D-CFTR produce cAMP-mediated chloride secretion in IB3-1 cells. Login to comment
115 A455E-CFTR-expressing cells showed results similar to wild type, although the induced currents were lower (Fig. 2C). Login to comment
116 The I-Vrelationship for A455E-CFTR-expressing cells was slightly outwardly rectified. Login to comment
121 The similarity between the currents of wild-type CFTR and A455E-CFTR and their differences from G551D-CFTR currents were evident from examination ofthe outwardly rectified versus linear current component for each (Fig. 3). Login to comment
123 Wild-type CFTR-expressing and A455E-CFTR-expressing cells also showed a significant increase (P < 0.05) in outwardly rectified current. Login to comment
124 Taken together, these results indicated that although an outwardly rectified, DIDS-sensitive current contributed to the whole cell currents in wild-type CFTR-expressing and A455E-CFTR-expressing cells, it did not con- 0 c) .., 500 A 400 300 200 100 0 500 ( < 400 0. Login to comment
129 (C) G551D-CFTR (Nonexp, n = 12; Exp, n = 5). Login to comment
130 (D) A455E-CFTR (Nonexp, n = 15; Exp, n = 6). Login to comment
150 On the other hand, DIDS, a compound that blocks the ORCC, inhibited a significant fraction of wild-type CFTR currents but had no effect on G551D-CFTR currents. Login to comment
151 The A455E mutation also alters CFTR function. Login to comment
153 Therefore, it is difficult to predict the molecular consequences of the A455E mutation. Login to comment
157 They found that A455E alters the processing of CFTR, and, when properly processed, A455E-CFTR functions as a chloride channel (30). Login to comment
158 In this study, A455E-CFTR-generated currents were about the same fraction (about two-thirds) of wild-type CFTR in both mammalian and Xenopus systems. Login to comment
159 This result indicates that if A455E causes a processing defect, it is not ameliorated by expression in Xenopus oocytes at 25°C. A455E-CFTR expressed in IB3-1 cells has both chloride channel and regulatory functions intact. Login to comment
160 Therefore, our data are consistent with the concept that A455E could cause a processing defect, which leads to decreased amounts of A455E-CFTR at the cell surface. Login to comment
161 A455E-CFTR that reaches the cell membrane appears to function similar to wild-type CFTR. Login to comment
163 Patients carrying A455E have been shown to be pancreatic sufficient, a situation that occurs with other partially functional mutants (31), but A455E also appears to be associated with mild lung disease (16, 17). Login to comment
164 This study demonstrates that A455E does not abolish the function of CFTR as a regulator, in particular as a regulator of the ORCC. Login to comment
167 The authors thank Dr. I. McIntosh for creating the G551D and A455E mutations, S. Allen for excellent technical assistance, J. Staton for secretarial assistance, and Genetic Therapy, Inc., for the gift of the pAvS6 vectors. Login to comment
26 To determine whether disease-associated mutations affect the regulatory function of CFTR, the functional consequences of two mutations, A455E and G551D, were studied. Login to comment
32 Our data suggest that CFTR bearing A455E can function as a cAMP-regulated chloride channel and also maintains its capacity to regulate the ORCC. Login to comment
36 The A455E mutation was created using the oligonucleotide 5'- GTTGTTGGAGGTTGCTGG-3'. Login to comment
45 The mutations, A455E and G551D, were created in pBQ4.7 (a generous gift from J. Rommens and L.-C. Tsui; The Hospital for Sick Children, Toronto) then shuttled to the pAvS6.CFTR or pRSV-CFTR by using Kpn2I and Hpa I (BRL) restriction sites common to all vectors. Login to comment
68 As seen in Fig. 1, oocytes injected with wild-type, G551D-, or A455E-CFTR generated cAMP-stimulated Cl-currents significantly greater than basal level. Login to comment
71 The currents in A455E-CFTR-injected oocytes were about 67% of wild-type, suggesting that A455E-CFTR forms a cAMP-activated chloride channel in Xenopus oocytes. Login to comment
76 |== I Control ~~ Fornkon +IBMX * Control Wild-type G551D A455E FIG. 1. Bar graph summary of Cl-currents (Icl) measured at a clamped voltage of -90 mV before and after stimulation with forskolin (10 ,uM) and IBMX (1 mM) for Xenopus oocytes injected with water (Control; n = 9), wild-type CFTR cRNA (n = 16), G551D-CFTR cRNA (n = 6), or A455E-CFTR cRNA (n = 6). Login to comment
85 IB3-1 cells were transfected with the RSV vector containing wild-type CFTR, G551D-CFTR, or A455E-CFTR. Login to comment
91 IB3-1 cells g+ DIDS were transiently transfected with + Glyb wild-type CFTR (A), G551D-CFTR (B), or A455E-CFTR (C). Login to comment
114 A455E-CFTR-expressing cells showed results similar to wild type, although the induced currents were lower (Fig. 2C). Login to comment
120 The similarity between the currents of wild-type CFTR and A455E-CFTR and their differences from G551D-CFTR currents were evident from examination ofthe outwardly rectified versus linear current component for each (Fig. 3). Login to comment
122 Wild-type CFTR-expressing and A455E-CFTR-expressing cells also showed a significant increase (P < 0.05) in outwardly rectified current. Login to comment
152 Therefore, it is difficult to predict the molecular consequences of the A455E mutation. Login to comment
156 They found that A455E alters the processing of CFTR, and, when properly processed, A455E-CFTR functions as a chloride channel (30). Login to comment
162 Patients carrying A455E have been shown to be pancreatic sufficient, a situation that occurs with other partially functional mutants (31), but A455E also appears to be associated with mild lung disease (16, 17). Login to comment
166 The authors thank Dr. I. McIntosh for creating the G551D and A455E mutations, S. Allen for excellent technical assistance, J. Staton for secretarial assistance, and Genetic Therapy, Inc., for the gift of the pAvS6 vectors. Login to comment

PMID: 7539891 [PubMed] Gan KH et al: "A cystic fibrosis mutation associated with mild lung disease."

No. Sentence Comment

29 Since the gene for cystic fibrosis was cloned, there have been several studies on associations between the genotype and the phenotype in cystic fibrosis.5-8 A number of mutations (R117H, R334W, R347P, A455E, and P574H) appear to be associated with pancreatic sufficiency9 and residual transmembrane transport of chloride.10,11 The most common mutation, ⌬F508, is associated with pancreatic insufficiency and severe pulmonary disease.5,6 There is great variation in the severity of lung disease, but until now no mutation associated with mild pulmonary disease has been found. Login to comment
30 Recently, we noted that a group of Dutch patients with cystic fibrosis who carried the A455E mutation had significantly better lung function than patients homozygous for the ⌬F508 mutation.12 An association between this mutation and exocrine pancreatic sufficiency has already been described.9,11 In addition, A455E appears to be associated with residual secretion of chloride in electrophysiologic studies of rectal-biopsy specimens.11 Among our patients the A455E mutation is relatively common and is associated with an older age at diagnosis.11,13 Because of the older age at diagnosis and the mutation-dependent residual chloride secretion associated with A455E, we hypothesized that the presence of this mutation could result in milder lung disease. Login to comment
34 Among the patients screened, 151 were found to be homozygous for the ⌬F508 mutation and 39 were found to have compound heterozygosity for the A455E mutation. Login to comment
35 In the A455E compound heterozygotes, the following mutations were found on the other allele: ⌬F508 (27 patients), 1717-1G→A (4 patients), E60X (4 patients), G542X (2 patients), R553X (1 patient), and an unknown mutation (1 patient). Login to comment
37 The other mutations found in A455E heterozygotes are all associated with pancreatic insufficiency and have been classified as severe cystic fibrosis mutations,8 predicted to produce no functioning CFTR.14 Therefore, all patients with an A455E allele were analyzed together. Login to comment
38 One patient, whose genotype was A455E/ ⌬F508, has been described elsewhere.15 This patient died at the age of 71 and could not be matched with a ⌬F508 homozygote because of her advanced age. Login to comment
39 No other data on deceased A455E compound heterozygotes were available, and therefore no data on deceased patients were included in the analysis of matched pairs. Login to comment
41 Analysis for the ⌬F508 mutation was carried out by direct polyacrylamide-gel electrophoresis of the CFTR exon 10 product of the polymerase chain reaction16 or as part of a multiplex amplification refractory mutation system.17 For the analysis of the A455E mutation, a specific amplification refractory mutation system was developed (Scheffer H, et al.: unpublished data). Login to comment
43 For A455E compound heterozygotes, the place of birth was recorded, as were the birthplaces and family names of their parents and grandparents, as far as could be ascertained. Login to comment
51 Statistical Analysis Each of the patients with the A455E mutation was matched with the ⌬F508 homozygote closest in age, within two years, and of the same sex. Login to comment
52 The patient who died at the age of 71 and four other A455E compound heterozygotes (40, 43, 53, and 47 years old, with the first three having a genotype of A455E/1717-1G→A and the fourth a genotype of A455E/⌬F508) could not be matched within two years of age with a ⌬F508 homozygote and were excluded. Login to comment
61 As far as could be determined, the families of the A455E compound heterozygotes were not related, nor did they come from geographically isolated regions. Login to comment
63 At least four A455E heterozygotes were former cigarette smokers, whereas none of the ⌬F508 homozygotes had ever smoked. Login to comment
66 The patients with the A455E mutation had significantly better lung function than did the ⌬F508 homozygotes (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; Pϭ0.002). Login to comment
67 The mean FVC was 88.7 percent for A455E compound heterozygotes and 76.3 percent for ⌬F508 homozygotes (Pϭ0.04). Login to comment
69 †The following genotypes were identified: A455E/⌬F508 (25 patients), A455E/E60X (4), A455E/G542X (2), A455E/R553X (1), and A455E/1717-1G→A (1). Login to comment
75 Characteristics of Pairs of ⌬F508 Homozygotes and A455E Compound Heterozygotes Matched According to Sex and Age. Login to comment
77 OF PAIRS ⌬F508 HOMOZYGOTES A455E COMPOUND HETEROZYGOTES† P VALUE Sex - no. Login to comment
81 (%) 33 9 (27.3) 0 0.004¶ Weight - (percentile)ʈ 33 61.0Ϯ29.4 53.4Ϯ30.3 NS Height - (percentile) Men 16 21.4Ϯ25.0 42.0Ϯ27.6 0.03‡ Women 17 38.1Ϯ28.2 38.7Ϯ29.4 NS less prevalent in patients with the A455E mutation, and diabetes mellitus was absent in this group (Pϭ0.004). Login to comment
83 The men with the A455E mutation, but not the women, were significantly taller than matched ⌬F508 homozygotes. Login to comment
85 The regression line had a slope of -0.0089 for A455E compound heterozygotes and a significantly steeper slope of -0.0178 for ⌬F508 homozygotes (Pϭ0.02). Login to comment
87 DISCUSSION The results of this study show that there is a relation between the presence of the A455E mutation and milder lung disease in patients with cystic fibrosis. Login to comment
88 Although the A455E mutation is known to be associated with pancreatic sufficiency,9 the association between A455E or any other cystic fibrosis mutation and milder lung disease has apparently not been found before. Login to comment
90 To overcome this problem, the Cystic Fibrosis Genotype-Phenotype Consortium initiated a large multicenter study that included 798 patients with cystic fibrosis.8 Of the eight mutations studied, none were associated with mild lung disease (A455E was not included). Login to comment
91 R117H, a mutation associated with residual transmembrane chloride transport,10 was also associated with an older age at diagnosis and with pancreatic sufficiency, but not with better lung function. Login to comment
92 The severity of disease in cystic fibrosis is determined by the mutation resulting in the least severe disease.9 All the A455E compound heterozygotes included in our study had a mutation on their other allele that was associated with severe disease. Login to comment
93 Mild symptoms in these patients are therefore most likely associated with the presence of the A455E mutation. Login to comment
97 FEV1 in 34 A455E Compound Heterozygotes and 130 ⌬F508 Homozygotes, According to Age. Login to comment
98 Solid squares represent patients included in the matched-pairs analysis; 4 A455E compound heterozygotes and 21 ⌬F508 homozygotes were not included because they were too young for pulmonary-function testing. Login to comment
100 The regression line had a slope of -0.0089 for A455E compound heterozygotes and -0.0178 for ⌬F508 homozygotes (Pϭ0.02). Login to comment
101 *Includes 31 A455E compound heterozygotes from the present study. Login to comment
105 Frequency of ⌬F508 and A455E Mutations in Various Countries. Login to comment
107 OF CHROMOSOMES SCREENED ⌬F508 A455E % Present study The Netherlands 556 73 7.0 Cystic Fibrosis Genetic Analysis Consortium33 The Netherlands* 1043 77.1 3.0 Lindner et al.34 Southwestern Germany 220 67 0 Cuppens et al.35 Belgium 200 72.5 1.0 Super and Schwarz36 Northwestern England 1008 82 0 Shrimpton et al.37 Scotland 506 72.3 0.5 Claustres et al.38 Southern France 262 63 0 Cutting et al.39 Baltimore 163 76.1 0.6 Cutting et al.,39 Zielenski et al.40 Toronto 1030 68.4 0.2 Rozen et al.31 Quebec 84 71 1 Rozen et al.31 Saguenay-Lac St. Jean, Quebec 182 58 8 Cutting et al.39 United States† 43 37 0 Cutting et al.39 Israel‡ 94 30 0 FEV1(%ofpredictedvalue) 140 120 100 80 60 40 20 0 706050403020100 A455E Compound Heterozygotes Age (years) FEV1(%ofpredictedvalue) 140 120 100 80 60 40 20 0 706050403020100 DF508 Homozygotes Age (years) Our results show that the type of mutation has a significant impact on pulmonary function in cystic fibrosis. Login to comment
108 Because of the relatively high frequency of the A455E mutation among our patients, we were able to include 33 patients, as compared with the 23 patients with the R117H mutation included in the consortium`s report.8 When sufficient numbers of patients are studied, it should be possible to show that other mutations associated with the preservation of pancreatic function and residual transmembrane chloride transport are also associated with milder pulmonary disease. Login to comment
109 A455E is a missense mutation that leads to a change from alanine to glutamic acid in amino acid residue 455 of the CFTR protein.27 CFTR is a chloride transporter driven by cAMP, and the A455E mutation is situated in the first nucleotide-binding fold, two residues removed from the so-called Walker-A motif, the proposed site of interaction with the phosphoryl moiety of the bound cAMP.28 The A455E mutation may interfere with the binding of cAMP to the CFTR protein. Login to comment
110 The CFTR protein coded for by the ⌬F508 mutation is subject to defective intracellular processing and does not reach the cell membrane, but is degraded intracellularly.29 The CFTR protein containing the A455E mutation may also be subject to this mechanism, but to a lesser degree.30 Unlike ⌬F508 homozygotes, patients with cystic fibrosis who have the A455E mutation have residual transmembrane chloride transport,11 a point that increases the likelihood that at least some functioning CFTR protein reaches the cell membrane. Login to comment
111 The A455E mutation was first found in patients from the Saguenay-Lac St. Jean region in northern Quebec.27,31 In this formerly isolated community, the incidence of cystic fibrosis and other inherited diseases is higher than normal.32 The A455E mutation is seldom found elsewhere in the world (Table 2),31,33-40 but it is relatively common in the Netherlands, where it is the second most common cystic fibrosis mutation (3.0 percent of all cystic fibrosis alleles).33 The two mutations that we studied, ⌬F508 and A455E, account for 80.1 percent of the mutations found in Dutch patients with cystic fibrosis. Login to comment
112 In our study the frequency of A455E was 7.0 percent, which may be related to the age distribution of our patients. Login to comment
113 In our patients, the presence of the A455E mutation was associated with the preservation of both endocrine and exocrine pancreatic function, less frequent colonization with P. aeruginosa, and mild lung disease. Login to comment
114 The regression line for FEV1 according to age was less steep in A455E compound heterozygotes than in ⌬F508 homozygotes, an indication that the progression of pulmonary disease is slower in patients with the A455E mutation. Login to comment
115 A455E is the first CFTR mutation for which an association with mild lung disease could be found. Login to comment
28 Since the gene for cystic fibrosis was cloned, there have been several studies on associations between the genotype and the phenotype in cystic fibrosis.5-8 A number of mutations (R117H, R334W, R347P , A455E, and P574H) appear to be associated with pancreatic sufficiency9 and residual transmembrane transport of chloride.10,11 The most common mutation, F508, is associated with pancreatic insufficiency and severe pulmonary disease.5,6 There is great variation in the severity of lung disease, but until now no mutation associated with mild pulmonary disease has been found. Login to comment
33 Among the patients screened, 151 were found to be homozygous for the F508 mutation and 39 were found to have compound heterozygosity for the A455E mutation. Login to comment
36 The other mutations found in A455E heterozygotes are all associated with pancreatic insufficiency and have been classified as severe cystic fibrosis mutations,8 predicted to produce no functioning CFTR.14 Therefore, all patients with an A455E allele were analyzed together. Login to comment
40 Analysis for the F508 mutation was carried out by direct polyacrylamide-gel electrophoresis of the CFTR exon 10 product of the polymerase chain reaction16 or as part of a multiplex amplification refractory mutation system.17 For the analysis of the A455E mutation, a specific amplification refractory mutation system was developed (Scheffer H, et al.: unpublished data). Login to comment
42 For A455E compound heterozygotes, the place of birth was recorded, as were the birthplaces and family names of their parents and grandparents, as far as could be ascertained. Login to comment
50 Statistical Analysis Each of the patients with the A455E mutation was matched with the F508 homozygote closest in age, within two years, and of the same sex. Login to comment
60 As far as could be determined, the families of the A455E compound heterozygotes were not related, nor did they come from geographically isolated regions. Login to comment
62 At least four A455E heterozygotes were former cigarette smokers, whereas none of the F508 homozygotes had ever smoked. Login to comment
65 The patients with the A455E mutation had significantly better lung function than did the F508 homozygotes (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; P0.002). Login to comment
70 ߤThe following genotypes were identified: A455E/F508 (25 patients), A455E/E60X (4), A455E/G542X (2), A455E/R553X (1), and A455E/1717-1G࢐A (1). Login to comment
76 Characteristics of Pairs of F508 Homozygotes and A455E Compound Heterozygotes Matched According to Sex and Age. Login to comment
78 OF PAIRS F508 HOMOZYGOTES A455E COMPOUND HETEROZYGOTESߤ P VALUE Sex - no. Login to comment
82 (%) 33 9 (27.3) 0 0.004&#b6; Weight - (percentile) 33 61.029.4 53.430.3 NS Height - (percentile) Men 16 21.425.0 42.027.6 0.03ߥ Women 17 38.128.2 38.729.4 NS less prevalent in patients with the A455E mutation, and diabetes mellitus was absent in this group (P0.004). Login to comment
84 The men with the A455E mutation, but not the women, were significantly taller than matched F508 homozygotes. Login to comment
86 The regression line had a slope of 0.0089 for A455E compound heterozygotes and a significantly steeper slope of 0.0178 for F508 homozygotes (P0.02). Login to comment
89 Although the A455E mutation is known to be associated with pancreatic sufficiency,9 the association between A455E or any other cystic fibrosis mutation and milder lung disease has apparently not been found before. Login to comment
94 Mild symptoms in these patients are therefore most likely associated with the presence of the A455E mutation. Login to comment
99 Solid squares represent patients included in the matched-pairs analysis; 4 A455E compound heterozygotes and 21 F508 homozygotes were not included because they were too young for pulmonary-function testing. Login to comment
102 *Includes 31 A455E compound heterozygotes from the present study. Login to comment
106 Frequency of F508 and A455E Mutations in Various Countries. Login to comment
116 The regression line for FEV1 according to age was less steep in A455E compound heterozygotes than in F508 homozygotes, an indication that the progression of pulmonary disease is slower in patients with the A455E mutation. Login to comment
117 A455E is the first CFTR mutation for which an association with mild lung disease could be found. Login to comment

PMID: 7541313 [PubMed] Schwiebert EM et al: "CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP."

No. Sentence Comment

126 (<3)Bar graphillustratingpercentcAMP-stimu- latedgenerationofglucose-6--32PinIB3-1cells, IB3-1 cellsstablytransfectedwithan AAVin- vertedterminalrepeatpromotor-drivenwild- typeCFTRviralvector(Eganetal, 1992;Flotte et al., 1993;Schwiebertet al., 1994a),or IB3-1cellstransientlytransfectedwithwild-typeor mutantCFTR(A455E-CFTRandG551D-CFTR).Data areexpressedtopercentchangeversuscontrol.Dataareexpressedasmean_ SEM.Numberinparenthesesisnumberofexperimentsperformed. Login to comment
145 Interestingly, two mutations located in the first nucleotide-binding domain of CFTR, A455E-CFTR, a mutation associated with mild CF pulmonary disease, and G551 D-CFTR, a mutation associated with severe CF lung disease, had different effects on the ability of CFTR to trigger ATP release. Login to comment
146 IB3-1 CF cells transientlytransfected with A455E reestablished cAMP-stimulated ATP release, although the magnitude was not as large compared with wild-type CFTR (Figure 4C). Login to comment
209 Further support for this hypothesis is that CFTR bearing an A455E mutation, which is associated with mild CF lung disease, can induce ATP release, whereas CFTR bearing a more severe G551D mutation fails to trigger ATP release. Login to comment
210 In a separate study, it was shown that both of the mutant forms of CFTR, A455E and G551D, could function as cAMP-activated CI- channels, although the function of G551D was much reduced compared with that of wild-type or A455E CFTR (Fulmer et al., 1995). Login to comment
211 Importantly, only A455E and not G551D could correct cAMP regulation of ORCCs in IB3-1 CF cells (Fulmer et al., 1995). Login to comment
130 (<3)Bar graphillustratingpercentcAMP-stimu- latedgenerationofglucose-6--32P inIB3-1cells, IB3-1 cellsstablytransfectedwithan AAVin- vertedterminalrepeatpromotor-drivenwild- typeCFTRviralvector(Eganetal, 1992;Flotte et al., 1993;Schwiebertet al., 1994a),or IB3-1cellstransientlytransfectedwithwild-typeor mutantCFTR(A455E-CFTRandG551D-CFTR).Data areexpressedtopercentchangeversuscontrol.Dataareexpressedasmean_ SEM.Numberinparenthesesisnumberofexperimentsperformed. Login to comment
149 Interestingly, two mutations located in the first nucleotide-binding domain of CFTR, A455E-CFTR, a mutation associated with mild CF pulmonary disease, and G551 D-CFTR, a mutation associated with severe CF lung disease, had different effects on the ability of CFTR to trigger ATP release. Login to comment
150 IB3-1 CF cells transientlytransfected with A455E reestablished cAMP-stimulated ATP release, although the magnitude was not as large compared with wild-type CFTR (Figure 4C). Login to comment
213 Further support for this hypothesis is that CFTR bearing an A455E mutation, which is associated with mild CF lung disease, can induce ATP release, whereas CFTR bearing a more severe G551D mutation fails to trigger ATP release. Login to comment
214 In a separate study, it was shown that both of the mutant forms of CFTR, A455E and G551D, could function as cAMP-activated CI-channels, although the function of G551D was much reduced compared with that of wild-type or A455E CFTR (Fulmer et al., 1995). Login to comment
215 Importantly, only A455E and not G551D could correct cAMP regulation of ORCCs in IB3-1 CF cells (Fulmer et al., 1995). Login to comment

PMID: 7578402 [PubMed] Crystal RG et al: "Evaluation of repeat administration of a replication deficient, recombinant adenovirus containing the normal cystic fibrosis transmembrane conductance regulator cDNA to the airways of individuals with cystic fibrosis."

No. Sentence Comment

112 G55 ID, S5491, A455E, and G542X account for 10-20% of ttie non-delta F508 mutations (33). Login to comment

PMID: 7543317 [PubMed] Pignatti PF et al: "Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis."

No. Sentence Comment

31 List of CFTR gene mutations and DNA polymorphisms screened Mutations R75Q/X/L, G85E, 394deITT 457TAT->G, R117H 621 + 1G->T 711 + 5G->A L206W 875 + 40 A->G 936 del TA 1001 + 11C->T R334W, R347 P/H/L, 1154insTC A455E, V456F DF5O8 1717-IG->A, 1717-8G->A G542X, G551D, Q552X, R553X P574H 1898 + 3A->G 2183 AA->G, 2184delA, R709X D836Y, 2694 T/G 2752-22 A/G 2789 + 5 G->A, 2790-2 A-»G Q890X 3041-71 G/C 3132delTG 3271 + 18 C-»T, 3272-26 A->G H1054D, G1061R, R1066C/H, A1067T, H1085R, Y1092X, 3320 ins5 D1152H R1162X, 3667ins4, 3737delA, 11234V 3849 + 10 kb C-»T, 3850-1 G-»A SI25IN, S1255P, 3905insT, 3898insC, D127ON, W1282X, R1283M, 4002 A/G 4005 + 1 G-»A N1303 K/H, 4029 A/G D1377H Q1411 X 4404 C/T, 4521 G/A Location e 3 e 4 i 4 i 5 e 6a i 6a e 6b i 6b e 7 e 9 e 10 i 10 e 11 e 12 i 12 e 13 e 14a i 14a i 14b e 15 i 15 e 17a i 17a e 17b e 18 e 19 i 19 e 20 i 20 e2l e 22 e 23 e24 Listing is in order of location along the CFTR gene, e = exon; i = intron. Login to comment
120 Several mutations were searched by restriction analysis: 457 TAT-»G, R334W, R347P/H/L, A455E, Q552X, 3849 + 10 kbC->T, D1270N. Login to comment

PMID: 7534226 [PubMed] Sheppard DN et al: "Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency."

No. Sentence Comment

1 To understand better how mutations in CFTR disrupt Cl- channel function and to learn about the relationship between genotype and phenotype, we studied two CF mutants, A455E and P574H, that are associated with pancreatic sufficiency. Login to comment
2 A455E and P574H are located close to conserved ATP binding motifs in CFTR. Login to comment
5 These mutants had normal or increased Cl- channel activity: A455E had an open-state probability (PO) similar to wild-type, and P574H had an increased PO because bursts of activity were prolonged. Login to comment
27 Two such mutations are located within NBD1: A455E and P574H (Kerem et al., 1990; Kristidis et al., 1992). Login to comment
28 Although these mutations are uncommon, A455E accounts for -10% of CF chromosomes in some areas of The Netherlands and in the Saguenay-Lac St Jean region of Quebec, Canada (Rozen et al., 1992; Gan et al., 1994). Login to comment
29 A455E and P574H affect residues in NBD1 that are located close to the Walker A (residues 458-464) and B (residues 568-572) motifs, respectively. Login to comment
31 Therefore, we tested the hypothesis that A455E and P574H might alter the function of CFTR Cl- channels. Login to comment
33 86 Oxford University Press Results Expression of A455E and P574H generates cAMP-activated CL currents To learn whether A455E and P574H could form regulated Cl- channels in epithelia, we expressed these mutants in cAMP~ N E ._0. -1 P574H cAMPI A455E 'cAMP 5 pA/cm2L 5 min b Fig. 1. cAMP agonists activate apical membrane CF- currents in FRT epithelia expressing A455E and P574H. Login to comment
44 Figure 1 shows that A455E and P574H generated cAMP-stimulated apical Cl- currents, but AF508 did not. Login to comment
45 However, the magnitude of current generated by A455E and P574H was <20% that of wild-type CFTR in the rank order: wild-type CFTR>> P574H > A455E > AF508. Login to comment
46 When we expressed A455E and P574H in HeLa cells and studied them with the whole-cell patch-clamp technique, we found properties qualitatively similar to those observed with wild-type CFTR (Welsh et al., 1992; Riordan, 1993). Login to comment
47 Figure 2 shows data from studies of P574H; similar results were obtained with A455E (data not shown). Login to comment
66 CFTR 0 * I1 -50 * CFTR A A455E * P574H pA Fig. 3. Login to comment
67 Single-channel properties of A455E and P574H. Login to comment
68 (A) Representative single-channel recordings are from excised inside-out membrane patches from HeLa cells transiently expressing wild-type CFTR, A455E or P574H. Login to comment
72 The voltages were -45 (CFTR), -46 (A455E) or -47 mV (P574H). Login to comment
73 (B) Single-channel I-V relationships of CFTR (U), A455E (A) and P574H (A). Login to comment
76 Conductance was CFT'R 7.76 ± 0.14, A455E 7.40 ± 0.25 and P574H 7.84 ± 0.26 pS; n = 6. Login to comment
81 Single-channel properties of A455E and P574H To determine why A455E and P574H generated less macroscopic Cl- current, we examined their single-channel properties in excised, inside-out patches of membrane. Login to comment
83 The tracings show that the single-channel current amplitudes of A455E and P574H were similar to that of wild-type CFTR. Login to comment
86 Figure 3A shows that A455E had a pattern of gating 878 that closely resembled that of wild-type CFTR. Login to comment
92 Figure 3C shows that the PO of A455E was similar to that of wild-type CFTR, whereas the PO of P574H was increased significantly. Login to comment
96 Maximum likelihood A 0.5pA 2s 50OC mV 0.6 PO 0.4 0.2- -0.1 - -1.2 0.0 J- - -0.4 A B pi (/S) al (f/S) pi 02I -- C2 _ ° a1 a2 12 CFTR A455E P574H CFTR A455E P574H Fig. 4. Login to comment
97 Effect of A455E and P574H on single-channel kinetics. Login to comment
100 (B) Effect of A455E and P574H on rate constants determined by the maximum likelihood fit to the model in (A). Login to comment
101 Data are from four CFTR, two A455E and six P574H single-channel patches. Login to comment
103 The voltages were -50 ± 2 (CFTR), -48 ± I (P574H) and -47 ± 1 mV (A455E). Login to comment
120 In two experiments we examined the gating kinetics of single phosphorylated A455E Cl- channels. Login to comment
121 A455E did not alter PI or al, but tended to increase P2 and a2 in both experiments (Figure 4B). Login to comment
124 Regulation of A455E and P574H by intracellular nucleotides Intracellular MgATP regulates CFTR through interactions with the NBDs. Login to comment
127 Therefore, we tested the hypothesis that ATP-dependent regulation of A455E and P574H was altered. Login to comment
129 At each concentration of MgATP tested, A455E had PO values similar to those of wild-type CFTR, whereas P574H had higher values of PO. Login to comment
131 Figure 5B shows that ADP (1 mM) produced an equivalent inhibition of wild-type CFTR, A455E and P574H. Login to comment
133 Analysis of the processing of A455E and P574H The data indicate that the reduced apical membrane Cl- current produced by A455E and P574H cannot be attributed to the reduced function of single mutant channels. Login to comment
139 However, band C production was reduced in A455E and P574H and was not apparent until 12-24 h after infection, and only then as a faint A B CFTR A455E P574H MgATP (mM) Fig. 5. Login to comment
140 Effects of MgATP concentration and ADP on the activity of phosphorylated A455E and P574H channels. Login to comment
142 and intracellular MgATP concentration for A455E, P574H and wild-type CFTR Cl- channels. Login to comment
143 Data points are the mean ± SEM of n = 4-6 for CFTR (-), n = 5 for A455E (A) and n = 3-5 for P574H (0) at each concentration. Login to comment
144 The voltages were -86 ± 1 (CFTR), -49 ± 2 (A455E) and -49 ± 1 mV (P574H). Login to comment
147 (B) Effect of intracellular ADP on the activities of CFTR, A455E and P574H Cl- channels. Login to comment
149 Values are the mean ± SEM of n = 4 for CFTR, A455E and P574H; the voltages were -49 ± 1 (CFTR), -48 ± 2 (A455E) and -52 ± 1 mV (P574H). Login to comment
150 Percent inhibition of NXP0 by 1 mM ADP was CFTR 77 ± 3, A455E 70 ± 3 and P574H 75 ± 6%. Login to comment
156 Although the production of mature band C protein was greatly reduced in A455E and P574H, it was greater than that observed with AF508. Login to comment
157 Discussion Relationship between apical membrane CL currents and the properties of mutant CFTR Because the A455E and P574H mutations cause CF, we hypothesized that Cl- transport would be reduced in cells expressing these mutants. Login to comment
161 If we set each of these variables to 100% for wild-type CFTR, we can then compare the apical Cl- current generated by wild-type and AF508 CFTR with that produced by A455E and P574H. Table I presents values of each variable, the predicted value of fCI(apical) determined by calculating N x i X P0 and the observed value of fCI(apical). Login to comment
164 Thus, these data provide a molecular explanation for the quantitative decrease in cAMP-stimulated apical membrane Cl- current generated by A455E and P574H. Table I. Login to comment
165 Comparison of predicted apical membrane Cl- current, N X i X PO, and measured cAMP-stimulated apical membrane Cl- current, f'(apical), for wild-type and mutant CFTR N i PO N X i X PO fl'(apical) (%) (%) (%) (%) (%) Wild-type 100 100 100 100 100 AF508 4 100 38 1.6 0 A455E 11 100 93 10.5 8 P574H 15 100 139 21.1 17 N, the number of Cl- channels in the apical membrane; i, single-channel current; PO- open-state probability. Login to comment
171 Mechanism of altered gating by A455E and P574H A455 and P574 lie near the conserved Walker A and B motifs of NBD1. Login to comment
177 It is interesting to compare the effect that different mutations in NBD1 had on al: P574H decreased a1, A455E did not change al, and K464A (a mutant of the Walker A lysine of NBDl; Carson and Welsh, 1995) appeared to increase the rate of channel closing. Login to comment
181 Expression of wild-type CFTR, AF508, A455E and P574H. Login to comment
187 The radioactivity in gels of immunoprecipitated and phosphorylated wild-type CFTR, AF508, A455E and P574H was quantitated as described in Materials and methods. Login to comment
188 The values are the mean + SEM of n = 3 for CFTR, AF508, A455E and P574H. Login to comment
190 It is interesting that A455E appeared to increase IP2 and a2, thereby increasing the frequency of transitions within a burst of activity. Login to comment
192 Our data from A455E, plus the finding that P574H altered P2, suggest that the NBDs may also be involved in regulating gating within a burst. Login to comment
193 One possible interpretation of the effect of A455E is that the mutation reduced the height of an energy barrier between the short-lived closed state (C2) and the open state. Login to comment
198 Our data indicate that processing mutations are not necessarily an all-or-none defect; in contrast to AF508, some of the mutant A455E and P574H protein had a glycosylation pattern consistent with processing in the Golgi complex and generated cAMP-stimulated apical Cl- currents. Login to comment
199 We evaluated the processing of A455E and P574H in HeLa and FRT cells incubated at 37°C. Login to comment
203 For example, A455E formed a channel that was misprocessed yet had conductive and regulatory properties very similar to those of wild-type CFTR. Login to comment
209 Implications for cystic fibrosis These data suggest that the mutations A455E and P574H cause CF because they disrupt the processing of CFTR and its delivery to the cell surface. Login to comment
210 However, they also suggest that these mutations are associated with a milder (PS) clinical phenotype because a small amount of the 881 CFTR A kDa 210 - 170- 116 - 98 - AF508 N. A455E I I P574H 4- Band C 4- Band B B band C bands A+B P574H aL mutant protein is processed correctly, retains normal or greater than normal Cl- channel function and thus generates residual cAMP-stimulated apical membrane C1- cur- rents. Login to comment
212 (1994) who demonstrated that rectal biopsies from patients bearing the A455E mutation retain residual Cl- secretion. Login to comment
215 (1994) found that patients with the A455E mutation were PS, but it is not clear whether or not the A455E mutation confers milder lung disease. Login to comment
216 Uncertainty about the severity of lung disease in these patients highlights the difficulty in assessing the clinical phenotype associated with the A455E and P574H1mutations in relatively small numbers of patients. Login to comment
220 These values are in the same range as those found for A455E (8%) and P574H (17%). Login to comment
223 A455E or P574H could prove to be of value in the development of therapies designed to augment the delivery to and the retention of mutant protein at the plasma membrane (Cheng et al., 1990; Lukacs et al., 1993). Login to comment
224 Although AF508 could be used to assess the processing defect, A455E or P574H might prove to be more tractable models for evaluating strategies to correct mislocalization because the processing defect is only partial and the conductance and regulation of the Cl- channels is more nearly normal. Login to comment
226 Such strategies might also be applied to patients bearing the A455E and P574H mutations because they appear to have at least some functional protein present in the plasma membrane. Login to comment
34 -1 P574H cAMPI A455E 'cAMP 5 pA/cm2L 5 min b Fig. 1. cAMP agonists activate apical membrane CF- currents in FRT epithelia expressing A455E and P574H. Login to comment
48 Figure 2 shows data from studies of P574H; similar results were obtained with A455E (data not shown). Login to comment
69 (A) Representative single-channel recordings are from excised inside-out membrane patches from HeLa cells transiently expressing wild-type CFTR, A455E or P574H. Login to comment
74 (B) Single-channel I-V relationships of CFTR (U), A455E (A) and P574H (A). Login to comment
77 Conductance was CFT'R 7.76 &#b1; 0.14, A455E 7.40 &#b1; 0.25 and P574H 7.84 &#b1; 0.26 pS; n = 6. Login to comment
82 Single-channel properties of A455E and P574H To determine why A455E and P574H generated less macroscopic Cl-current, we examined their single-channel properties in excised, inside-out patches of membrane. Login to comment
84 The tracings show that the single-channel current amplitudes of A455E and P574H were similar to that of wild-type CFTR. Login to comment
87 Figure 3A shows that A455E had a pattern of gating 878 that closely resembled that of wild-type CFTR. Login to comment
93 Figure 3C shows that the PO of A455E was similar to that of wild-type CFTR, whereas the PO of P574H was increased significantly. Login to comment
98 Effect of A455E and P574H on single-channel kinetics. Login to comment
102 Data are from four CFTR, two A455E and six P574H single-channel patches. Login to comment
104 The voltages were -50 &#b1; 2 (CFTR), -48 &#b1; I (P574H) and -47 &#b1; 1 mV (A455E). Login to comment
122 A455E did not alter PI or al, but tended to increase P2 and a2 in both experiments (Figure 4B). Login to comment
125 Regulation of A455E and P574H by intracellular nucleotides Intracellular MgATP regulates CFTR through interactions with the NBDs. Login to comment
128 Therefore, we tested the hypothesis that ATP-dependent regulation of A455E and P574H was altered. Login to comment
130 At each concentration of MgATP tested, A455E had PO values similar to those of wild-type CFTR, whereas P574H had higher values of PO. Login to comment
132 Figure 5B shows that ADP (1 mM) produced an equivalent inhibition of wild-type CFTR, A455E and P574H. Login to comment
134 Analysis of the processing of A455E and P574H The data indicate that the reduced apical membrane Cl-current produced by A455E and P574H cannot be attributed to the reduced function of single mutant channels. Login to comment
141 Effects of MgATP concentration and ADP on the activity of phosphorylated A455E and P574H channels. Login to comment

PMID: 8825494 [PubMed] Zielenski J et al: "Cystic fibrosis: genotypic and phenotypic variations."

No. Sentence Comment

551 FIBROSIS Table 1 Most common CFTR mutations in the world Name of Mutation �F508 0542X 0551D NI303K WI282X R553X 621 + 10 � T 1717-10 � A RI17H R1162X R347P 3849 + IOkbC � T �1507 394delTT 085E R560T A455E 1078deiT 2789 + SO � A 3659deiC R334W 1898 + 10 � T 711 + 10 --. Login to comment
628 This strategy may also be applied to patients with other Normal II III IV V No synthesis Block in Block in Altered Reduced processing regulation conductance synthesis Nonsense Missense G542X Missense Missense Missense A455E Frameshift N1303K G551D R117H 394deiTT AA deletion Alternative L1F508 R347P splicing Splice junction 1717-1G-->A 3849+1OkbC-->T Figure 3 Molecular consequence of different classes ofCF mutations. Login to comment
644 Several missense mutations (e.g. P574H and A455E) are reasoned to have mild molecular consequence because they are found associated with pancreatic sufficiency-a mild phenotype (lOS). Login to comment
654 One study based on a small number of PS patients suggests a correlation between A455E mutation and mild pulmonary presentation (76). Login to comment

PMID: 7525450 [PubMed] Dork T et al: "Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients."

No. Sentence Comment

77 Table 1 Frequency distribution and haplotypes of CFTR mutations in 700 German CF chromosomes Mutation~ Nucleotide changesb Locationc Frequencyd Haplotype~ Referencef Q39x C--~T at 247 Exon 2 1 (0.1%) D3 Cutting et al. (1992) E60X G-+T at 310 Exon 3 1 (0.1%) A2 Malone et al. (*) R75X C--+T at 355 Exon 3 1 (0.1%) C2 This study 405+1 G---~A G-+A at 405+1 Intron 3 1 (0.1%) C2 D6rk et al. (1993c) E92X G--~T at 406 Exon 4 2 (0.3%) B2 Will et al. (1994) R117C C---~Tat 481 Exon 4 1 (0.1%) C2 This study R117H G--+A at 482 Exon 4 2 (0.3%) B6 Dean et al. (1990) 621+1 G--+T G--+T at 621+1 Intron 4 1 (0.1%) B1 Zielenski et al. (1991b) H199Y C--+T at 727 Exon 6a 1 (0.1%) A2 This study (*) 1078delT Deletion of T at 1078 Exon 7 4 (0.6%) C2 Claustres et al. (1992) R334W C-~T at 1132 Exon 7 2 (0.3%) BI Gasparini et al. (1991) 1336K T-->A at 1139 Exon 7 3 (0.4%) A2 Cuppens et al. (1993) R347P G--+C at 1172 Exon 7 11 (1.6%) A2, C2 Dean et al. (1990) 1342-2 A--+C A--+C at 1342-2 Intron 8 3 (0.4%) A4 D/3rk et al. (1993b) Q414X C--+T at 1372 Exon 9 1 (0.1%) D3 D6rk et al. (1994a) A455E C-+A at 1496 Exon 9 1 (0.1%) BI Kerem et al. (1990) V456F G--~T at 1498 Exon 9 1 (0.1%) B3 D6rk et al. (1994a) A1507 Deletion of 3 bp between 1648-1653 Exon 10 1 (0.1%) D5 Kerem et al. (1990) AF508 Deletion of 3 bp between 1652-1655 Exon 10 504 (72.0%) B1, DI, B7 Kerem et al. (1989) 1717-1 G--+A G--+A at 1717-1 lntron 10 6 (0.9%) B3 Kerem et al. (1990) G542X G--+T at 1756 Exon 11 10 (1.4%) B1 Kerem et al. (1990) G551D G--+A at 1784 Exon 11 7 (l.0%) B3 Cutting et al. (1990) Q552X C-+T at 1786 Exon 11 1 (0.1%) A4 Devoto et al. (1991) R553X C--+T at 1789 Exon 11 16 (2.3%) A4, B4, D3 Cutting et al. (1990) L558S T--+C at 1805 Exon 11 1 (0.1%) C2 Maggio et al. (*) 1811+I.6kBA-+G A--+Gat 1811+l.6kB lntron 11 1 (0.1%) A2 Chillonetal. Login to comment

PMID: 7522998 [PubMed] Tsongalis GJ et al: "Association of pancreatic adenocarcinoma, mild lung disease, and delta F508 mutation in a cystic fibrosis patient."

No. Sentence Comment

44 CorrelatIon of phenotype and genotype of CFTR mutations Key phenotypic Lung disease SweatC1 Exocnne pancreas function Vasdeferens Associated CFTR mutations Pancreatic InsuffIcIent Pancreatic sufficient Normalsweat C1 Severe Less severe Relatively mild Elevated Elevated Normal Insufficient Sufficient Sufficient Absent Absent Absent SF508, G542X, R553X, G5510, Ni 303K, Wi 282X, RI 17H, and others 2789 + 5G>A, R117H, R334W, R347P, A455E, P574H, S945L, G85E, and others G551S, R117H, 3849 + 10kb C>T, and others Congenitalabsence of the vas deferens None Normal or elevated Sufficient Absent F508C, Ri 17H, Di D1152H, and others FIg. 2. Login to comment

PMID: 7525963 [PubMed] Chevalier-Porst F et al: "Mutation analysis in 600 French cystic fibrosis patients."

No. Sentence Comment

21 Among the 104 other CFTR mutations tested on the 373 non-AF508 CF chromosomes, none of the following 58 mutations were found: G91R, 435 insA, 444delA, D11OH, 556delA, 557delT, R297Q, 1154insTC, R347L, R352Q, Q359K/T360K, 1221delCT, G480C, Q493R, V520F, C524X, 1706dell7, S549R (A-C), S549N, S549I, G551S, 1784delG, Q552X, L558S, A559T, R560T, R560K, Y563N, P574H, 2307insA, 2522insC, 2556insAT, E827X, Q890X, Y913C, 2991de132 (Dork et al, personal communication), L967S, 3320ins5, 3359delCT, H1085R, R1158X, 3662delA, 3667del4, 3667ins4, 3732delA, 3737delA, W1204X, 3750delAG, I 1234V, Q1238X, 3850- 3T-+G, 3860ins31, S1255X, 3898insC, D1270N, R1283M, F1286S, 4005 + I G-A. Forty-six other mutations were found on at Distribution of CFTR mutations found in our sample ofpopulation (1200 CF chromosomes) Mutations tested No of CF chromosomes Haplotypes Method with the mutation XV2C-KM19 (% of total CF alleles) Exon 3: G85E 4 (033) 3C HinfI/ASO394delTT 2 2B PAGEExon 4: R117H 1 B ASOY122X 2 2C MseI/sequenceI148T 1 B ASO621+IG-J* 1 B MseIIASOExon 5: 711+1G--T 8(07) 8A ASOExon 7: AF311 1 C PAGE/sequencelO78delT 5 (0-42) 5C PAGE/ASOR334W 5 (0-42) 2A,2C,ID MspIlASOR347P 5 (042) 5A CfoI/NcoIR347H 1 Cfol/sequenceExon 9: A455E 1 B ASOExon 10: S492F I C DdeI/sequenceQ493X 1 D ASOl609deICA 1 C PAGE/Ddel/sequenceA1507 3 (025) 3D PAGE/ASOAF508 827 (69) 794B,30D,2C,IA PAGEl677delTA 1 A PAGE/sequenceExon I11: 1717-IG--.A 16(1-3) 14B Modified primers + AvaIIG542X 40 (3-3) 29B,5D,2A Modified primers + BstNiS549R(T--*G) 2 2B ASOG551D 3 (025) 3B HincII/Sau3AR553X 10(0-8) 6A,1B,2C,ID Hincll/sequenceExon 12: 1898+IG--A 1 C ASO1898+ IG-C 2 IC ASOExon 13: l9l8deIGC 1 A PAGE/sequence1949de184 I C PAGE/sequenceG628R(G-+A) 2 2A Sequence2118de14 I c PAGE/sequence2143de1T 1 B PAGE/modified primers2184de1A+2183A--*G 11 (0-9) lIB PAGE/ASO2184de1A 1 ASOK710X 3 (025) IC XmnI2372de18 1 B PAGE/sequenceExon 15: S945L 1 C TaqlExon 17b:L1065P I MnlIL1077P 1 A ASOY1092X 3 (025) 2C,IA Rsal/ASOExon 19: RI1162X 6 (0-5) 5C,IA DdeI/ASO3659delC 3 (025) 3C ASOExon 20: G1244E 2 2A MboIIS1251N 2 2C RsaI3905insT 4 (0-33) 4C PAGE/ASOW1282X 18 (105) 15B,1D MnlI/ASOR1283K 1 C Mnll/sequenceExon 21: N1303K 22 (1-8) 18B,lA,ID Modified primers+BstNI 47 mutations 1031 (85 9) least one CF chromosome (table): 21 of them are very rare as they were found on only one CF chromosome in our population. Login to comment

PMID: 7520797 [PubMed] Cuppens H et al: "CFTR haplotype backgrounds on normal and mutant CFTR genes."

No. Sentence Comment

34 Distribution of alleles at 10 polymorphic loci Locus Allele Normal Mutant Mutations XV2c KM19 D9 1 2 1 2 1 2 58 (0.492) 60 (0.508) 84 (0.622) 51 (0.378) 78 (0.586) 55 (0.414) 146 (0.918) 13 (0.082) 19(0.109) 156 (0.891) 15 (0.085) 161 (0.915) 1001 + llC/T Tn 115 (0.927) R 9 (0.073) 5 7 (0.057) 7 102 (0.836) 9 13 (0.107) M470V C 62 (0.496) R 63 (0.504) 1898+15 2T/A C 84(0.641) R 47 (0.359) T854T Q1463Q D7S8 C 82 (0.636) R 47 (0.364) C 90 (0.692) R 40 (0.308) 1 38 (0.317) 2 82 (0.683) 33 (0.192) 139 (0.808) 0 (0.000) 32 (0.190) 136 (0.810) 156 (0.902) 17 (0.098) 163 (0.926) 13 (0.074) 162 (0.926) 13 (0.074) 162 (0.931) 12 (0.069) 91 (0.569) 69 (0.431) E60X, 622-2A-C, A455E, AF508 (98.3%), 1717-1G-A, G542X, 0.479 63.54 G628R(G-C)/S1235R,2183AA-G, G970R, W1282X, N1303K p<10~ G458V, AI5O7, AF508 (1.7%), 1898 + 1G-C, E73OX, 3272-26A-G, W1310X, 4218insT, UA, UB, UC I336K, W401X, 2T2ldelll, Y1092X, 3659delC, S1251N: not included (5%) E60X, 622-2A-C, W401X, G458V, AF5O8 (1.6%), 1898+ 1G-C, -0.541 90.63 G628R(G-Q/S1235R, E730X, G970R, 3272-26A-G (50.0%), p<10" Y1092X, 3659delC, S1251N, W1310X, UB, UTC A455E, AI507, AF5O8 (98.4%), 1717- 1G-A, G542X, 2183AA-G, 3272-26A-G (50.0%), W1282X, N13O3K, 4218insT, UA 1336K, 2721delU: not included (1%) E60X, 622-2A-C, W401X, G458V, 1898 +1G-C, E730X, G970R, -0.541 90.46 Y1092X, 3659delC, S1251N, W1310X, UB, UC p<10" A455E, AI507, AF508, 1717- 1G-A, G542X, G628R(G-Q/S1235R, 2183AA-G, 3272-26A-G, W1282X, N13O3K, 4218insT, UA I336K, 2721delll: not included (1%) E60X, 622-2A-C, I336K, W401X, G458V, AI507, 1717- 1G-A, -0.726 155.94 1898 + 1G-C, G628R(G-C)/S1235R, 2183AA-G, E730X, 2721delll, p< 10" G970R, 3272-26A-G, Y1092X, 3659delC, S1251N, W1282X, W1310X, 4218insT, UA, UB, UC A455E, AF5O8, G542X, N13O3K E60X, 622-2A-C, I336K, W401X, G458V, AI507, 1717-1G-A, 1898 + 1G-C, G628R(G-C)/S1235R, 2183AA-G, E730X, 2721delll, G970R, 3272-26A-G, Y1092X, 3659delC, S1251N, W1282X, W1310X, 4218insT, UA, UB, UC A455E, AF5O8, G542X, N13O3K A455E, AI5O7, AF508, 1717-1G-A, G542X, G628R(G-Q/S1235R, 2183AA-G, 3272-26A-G, W1282X, N13O3K, 4218insT, UA E60X, 622-2A-C, W401X, G458V, 1898 + 1G-C, E730X, G970R, Y1092X, 3659delC, S1251N, W1310X, UB, UC 1336K, midclll: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF508 (99.2%), G542X, 1898 + 1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC, S1251N, N1303K, W1310X, UB, UC AI507, AF5O8 (0.8%), 1717-1G-A, G628R(G-Q/S1235R, 3272-26A-G, W1282X, 4218insT, UA I336K, 2721delU: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF508 (99.2%), G542X, 1898+1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC,S1251N, N13O3K, W1310X, UB, UC AI507, AF508 (0.8%), 1717-1G-A, G628R(G-C)/S1235R, 3272-26A-G, W1282X, 4218insT, UA 1336K, midelll: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF5O8 (99.2%), G542X, G628R(G-Q/S1235R, 2183AA-G, E730X, G970R, Y1092X, 3659delC, S1251N,N1303K, W1310X, UC AI507, AF5O8 (0.8%), 1717-1G-A, 1898 + 1G-C, 3272-26A-G, W1282X, 4218insT 1336K, 2721del11. Login to comment
35 UA, UB: not included (2%) A455E, AF508 (61.2%), 1717-1G-A (66.7%), G542X, G628R(G-C)/S1235R, 3272-26A-G, S1251N, W1282X, W1310X E60X, 622-2A-C, W401X, G458V, AJ507, AF5O8 (38.8%), 1717- 1G-A (33.3%), 1898 +1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC, N13O3K, 4218insT, UA, UB, UC 1336K, 2721delll: not included (1%) -0.694 139.81 p<10~ 0.452 60.83 p<10" 0.355 38.77 p<10" 0.360 39.44 p<10~7 0.314 29.91 0.250 17.54 p<10"4 The observed CFTR genes associated with a particular allele are given, proportions are given between brackets. Not all the mutations were informative for each of the tested loci, which were therefore not included. For the Tn locus the standardized linkage disequilibrium coefficient was calculated for the group of the non-T9 alleles and the T9 alleles. Login to comment
72 Extragenic (XV2c/KM19/D9) haplotypes Haplotype Normal Mutant Mutations 111 211 121 112 212 122 222 23 (0.204) 43 (0.381) 2 (0.018) 6 (0.053) 0 (0.000) 22 (0.195) 17 (0.150) 4 (0.026) E60X, 622-2A-C, G970R 6 (0.039) G458V, 1898+1G-C, E73OX, W1310X, UB, UC 0 (0.000) 3 (0.019) AF5O8 (1.7%), G628R(G-Q/S1235R 1 (0.006) 3272-26A-G (50.0%) 134 (0.870) A455E, AF508 (96.5%), 1717-1G-A, G542X, 2183AA-G, W1282X, N13O3K 6 (0.039) AI507, AF508 (1.8%), 3272-26A-G (50.0%), 4218insT, UA p<10"3 p<10"7 p<10~7 p<10"2 The observed CFTR genes associated with a particular haplotype are given, proportions are given between brackets. Login to comment
103 CFTR haplocypes I II ma mb rv V VI Haplotype C7RCCC 211C7RCCC1 111C7RCCC1 /11C7RCCC1 211C7RCCC2 111C7RCCC2 /11C7RCCC2 122C7RCCC2 121C7RCCC2 C5CRRR 122C5CRRR1 211C5CRRR2 222C5CRRR2 C7CRRR 122C7CRRR1 222C7CRRR1 212C7CRRR1 122C7CRRR2 222C7CRRR2 122C7CRRR/ C9CRRR 211C9CRRR1 R9CCCC 122R9CCCC1 222R9CCCC1 /22R9CCCC1 112R9CCCC1 122R9CCCC2 222R9CCCC2 112R9CCCC2 R9CRRR 122R9CRRR1 C7CRRC 112C7CRRC1 112C7CRRC2 C9CRRC 211C9CRRC1 C7CCCC 211C7CCCC1 222C7CCCC1 122C7CCCC2 C7RCCR 211C7RCCR2 Normal 0.524 (43) 0.085 0.073 0.195 0.146 0.012 0.012 0.049 (4) 0.012 0.024 0.012 0.220 (18) 0.024 0.073 0.000 0.073 0.049 0.012 (1) 0.012 0.073 (6) 0.000 0.000 0.000 0.061 0.012 0.000 0.000 (0) 0.000 0.061 (5) 0.000 0.061 0.012 (1) 0.012 0.037 (3) 0.012 0.024 0.000 0.012 (1) 0.012 Mutant 0.080 (IS) 0.005 0.000 0.020 0.015 0.020 0.020 0.000 0.000 0.000 (0) 0.000 0.000 0.000 Mutations p<10"7 W1310X S1251N G458V, E730X, UC E60X, 622-2A-C, G970R W401X, Y1092X, 3659delC 0.055 (9) p<10"2 0.017 0.005 0.005 0.008 0.010 0.010 0.000 (0) 0.000 1717-1G-A (66.7%) 50.0% of 3272-26A-G 50.0% of 3272-26A-G 1717-1G-A(33.3%) AI507, 4218insT W1282X 0.819 (130) p<10~7 0.466 0.007 0.010 0.007 0.312 0.007 0.007 0.005 (1) 0.005 0.005 (1) 0.005 0.000 0.000 (0) 0.000 0.010 (2) 0.000 0.000 0.010 0.005 (1) 0.005 56.7% of AF508, G542X 1% of AF5O8 A455E 1% of AF5O8 38.1% of AF508, N1303K 1.0% of AF5O8 1% of AF508 1% of AF508 G628R(G-Q/S1235R 2183AA-G 1898+1G-C The proportion of CFTR genes associated with a particular haplotype, and the mutations found to be associated with that haplotype are given. Login to comment
134 The 3 most frequent mutations together with the A455E mutation were associated with allele R, all other CFTR mutations were associated with allele C. Login to comment
150 The 4 mutations that were also associated with the R allele at the 1001 + 11C/T locus were associated with the 9T allele, i.e. the three most common CF mutations and the A455E mutation. Login to comment
151 The A455E mutation is located in exon 9 itself, in which only a limited number of mutations have been identified. Login to comment
153 A major difference between these two mutations is that G458V is considered as a severe mutation (23), while A455E is known as a mild mutation with regard to pancreatic involvement (10). Login to comment

PMID: 7505767 [PubMed] Dork T et al: "Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations."

No. Sentence Comment

61 Association of (TG),Tm alleles with CFTR mutations (TG),Tm CFTR mutationsa (TG)llT7 E60X, E92X, R117C, 1078delT, R347P, R553X, 2184delA, 2184insA, I1005R, 3272-26A--~G, L1059X, Y1092X, R1162X, 3659delC, 3850-3T-oG, S1251N Q39X, R117H, Q414X, V456F, AI507, 1717-1G--~A, G551D, 2043delG, 2183AA---~G, 2184insA, 2789 + 5 G---~A,3272-26A---~G, R1066C, L1077P, 3849 + l0 kB C---~T,4374 + 1 G---~T 621 + 1 G---~T,R334W, A455E, AF508, G542X, 2143delT, 3849 + 10 kB C---~T,NI303K 405 + 1 G----~A,1342-2 A---~C,R553X (TG)IoT7 (TG)10T9 (TG)12T7 a References are compiled in Tsui (1992), except for 2143delT (Dtrk et al. 1992b), 3850-3 T---~G,4374 + 1 G---~T,1342-2 A---~C (Dtrk et al. 1993a, b), Q414X, V456F (this work), 405 + 1 G---~A, E92X, R117C, 2184delA, 2184insA, I1005R, L1059X (T. Login to comment
75 The missense mutations A455E and V456F are both located in front of the conserved Walker motif A (Riordan et al. 1989; Walker et al. 1982). Login to comment
76 A455E has previously been described (Kerem et al. 1990) and is reported to be frequent in French-Canadians (Rozen et al. 1992). Login to comment
77 We confirmed A455E in a single German CF female with AF508 on her other chromosome. Login to comment
81 The mutations A455E and V456F both destroy the same recognition site for the restriction enzyme AciI. Login to comment
115 Early evidence for a crucial role of exon 9 sequences came from the findings that mutations 71 within or adjacent to the Walker motif A produce a CF phenotype in vivo (A455E, G458V; Kerem et al. 1990; Cuppens et al. 1990) and in vitro (K464A; Anderson and Welsh 1992). Login to comment

PMID: 7508414 [PubMed] Cuppens H et al: "Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene."

No. Sentence Comment

43 TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment
48 The G628R(G --~ C) and $1235R mutations were found on a single allele; the W1310X allele and one 2184delA (plus A --~ G at 2183) allele were found on a CFTR gene from Turkish descent. Login to comment
49 For each type mutation, at least one allele was completely sequenced: 14 for AF508, 3 for G542X, 2 for 1717-1G -~ A, 1 for A455E, 1 for G458V, 1 for AI507, 1 for W1282X, 1 for N1303K, and for the remainder, the total number of alleles that were found in this study. Login to comment
105 The fact that the G458V/G542X individual has CF suggests that the alternatively spliced 9- CFTR mRNA transcript cannot compensate for the basic defect of the CFTR protein in this CF patient. Login to comment
106 This was also seen in another CF patient, who was a compound heterozygote for the A455E and Y1092X mutations, A455E also being located in exon 9. Login to comment
107 The A455E allele carried nine thymidines in its poly-(T) tract. Login to comment
108 The parent of the A455E/Y1092X compound heterozygote, carrying the A455E allele, carried five thymidines in the poly-(T) tract on the normal CFTR allele (data not shown). Login to comment
42 TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment

PMID: 7682984 [PubMed] Guillermit H et al: "A novel mutation in exon 3 of the CFTR gene."

No. Sentence Comment

63 Other missense mutations reported by Kristidis et al. (1991) as being located in the transmembrane domain, i.e. R117H (exon 4), R334W (exon 7), R347P (exon 7), A455E (exon 9) and P574H (exon 12), are associated with pancreatic sufficiency; these observations are consistent with the genetic hypothesis that pancreatic sufficiency is a 235 dominant phenotypic trait associated with about 10% of the CF alleles. Login to comment

PMID: 7678316 [PubMed] Kubesch P et al: "Genetic determinants of airways' colonisation with Pseudomonas aeruginosa in cystic fibrosis."

No. Sentence Comment

90 The association between exocrine pancreatic function and genotypematched for 11 genotypes, the exception being the DgrF508/A455E compound heterozygotes (Hannover 1PI, Toronto 2PS). Login to comment

PMID: 1384327 [PubMed] Scriver CR et al: "Cystic fibrosis genotypes and views on screening are both heterogeneous and population related."

No. Sentence Comment

78 Ten alleles at 0.27% each .................... Total ............................................ French Canadians from northeastern Quebec (Rozen et al. 1992 [181]): 48 30 12 4 3 97 60 22 4 0 4 92a 82 4 1 1 1 2 3 98a AFS08 ......... ..................... 58 621+1G-T .............................. 23 A455E .......... .................... 8 G85E ......... ..................... 1 711+1 G-T ............................... 1 G542X .......... .................... 1 Y1092X .............................. 1 N1303K ........... ................... 1 Total .......... .................... 93a a Because of rounding, individual values do not sum to the total. Login to comment

PMID: 1283148 [PubMed] Lindner M et al: "The spectrum of CFTR mutations in south-west German cystic fibrosis patients."

No. Sentence Comment

4 Another 5 mutations accounted for a further 12.5% (4% G542X; 3% R553X; 3% N1303K; 2% 1717-1 G--~A; 0.5% G551D) whereas 6 mutations (R117H, A455E, AI507, $549I, $549N, and R1162X) were not found. Login to comment
26 The R117H, A455E, 1717-1G~A, AF508, G542X, G551D, and NI303K mutations were identified by allele specific oligonucleotide hybridisation (ASO, Sambrook et al. 1989) using 32p-labelled probes specific for the normal or the mutated sequence (Table 1). Login to comment
34 Mutations observed in 220 defective cystic fibrosis transmembrane conductance regulator (CFTR) alleles Mutation n (%) Rll7H 0 A455E 0 AI507 0 AF508 147 (67) 1717-1G--*A 4 (2) G542X 9 (4) $549I 0 $549N 0 G551D 1 (<0.5) R553X 7 (3) R1162X 0 N1303K 6 (3) Unknown 46 (21) Total 220 (100) patients in that group R553X was considerably more common than G542X (Plieth et al. 1992). Login to comment
48 We are grateful to Professor Kubanek for his continuous support, to Professor Kaiser, Pforzheim for sending blood samples and providing clinical information on some of his patients, and to Dr.M. Schwarz, Royal Manchester Children's Hospital, for providing allele specific oligonucleotides for the R117H, A455E and 1717-1G--~A mutations together with the appropriate controls. Login to comment

PMID: 1279852 [PubMed] Tsui LC et al: "The spectrum of cystic fibrosis mutations."

No. Sentence Comment

64 Frequent cystic fibrosis mutations Name Relative freqeenc~ Mutation Con~,~'~luence Ref. Z~508 67.2 G542X 3.4 G551D 2.4 W1282X 2.1 3905insT 2.1 N1303K 1.8 3849+10kbC-+T 1.4 1717-1G-+A 1078delT 2789+5G--+A Deletion of 3 bp between nt 1652 and t655 in exon 10 G-+T at nt 1756 in exon 11 G-+A at nt 1784 in exon 1I G-+A at nt 3978 in exon 20 Insertion of T after nt 3905 in exon 20 C-+G at nt 4041 in exon 21 C-->T in a 6.2 kb EcoRI fragment 10 kb from 5' junction of intron 19 3849+4A-+G 1.0 7tt÷IG--+T 0.9 Rl162X 0.9 1898+lG-+A 0.9 Rll7H 0.8 3659delc 0.8 G85E 0.7 2184delA 0.7 AI5W 0.5 R347P 0.5 R~ 0.4 1,3 C-+T at nt 1"789in exon 11 1.3 G-+T at nt 1 from 5' junction of intron 4 1.1 G--+A at nt 1 from 3' junction of intron 10 1.1 Deletion of T at nt 1078 in exon 7 1.1 G-cA at 5 nt from 5' end of intron 14b A-->G at 4 nt from 5' end of intron 19 G-+T at nt 1 from 5' junction of intron 5 C-+T at nt 3616 in exon 19 G-+A at nt 1 from 5' junction of intron 12 G--)A at nt 482 in exon Deletion of C at nt 3659 in exon 19 G-+A at nt 386 in exon 3 A-->G at nt 2183 and deletion of A at nt 2184 in exon 13 Deletion of 3 bp between nt 1648 and 1653 in exon 10 G-+C at nt 1172 in exon 7 G-~C at nt 1811 in exon 11 A455E 0.4 R334W 0.4 Y122X 0.3 S549R(T-+G) 0.3 Q493X 0.3 V520F 0.2 S549N 0.2 C-+A at nt 1496 in exon 9 C-+T at nt 1132 in exon 7 T-cA at nt ~i98 in exon 4 T--+G at nt 1779 in exon 11 C-+T at nt 1609 in exon 10 G-+T at nt 1690 in exon 10 G-->A at nt I778 in exon !1 Deletion of Phe at codon 508 Gly-+Stop at codon 542 12 Gly-~Asp at codon 551 10 l"rp-->Stop at codon t282 35 Frameshift -~ Asn-+Lys at codon 1303 36 Aberrant splicing -~ Arg~Stop ~ codon 553 Splice mutation 10 37 Splice mutation 12 Frameshift 38 Splice mutation _c Splice mutation? Login to comment
122 This hypothesis has been well supported by analysis of patients, which shows that individuals with one or two copies of the missense alleles such as Rll7H, R334W, R347P, A455E (Ref. 12) or P574H (Ref. 12) are found to be PS, whereas those with two copies of nonsense, frameshift, splice-site or a subset of the missense mutations are invariably PI TIGNOVEMBER1992 VOt. Login to comment

PMID: 1281032 [PubMed] Super M et al: "Milestones in cystic fibrosis."

No. Sentence Comment

164 Mutations encountered elsewhere in UK but not yet m N-W 1154insTC R347P A455E G458V Q493X C524X S549N R1283M Q1291H 199 (in the north-west group) 199 199 0 0 0 199 199 0 icant alteration in function appears to be worse than no CFTR being formed at all. Login to comment

PMID: 1382071 [PubMed] Montrose-Rafizadeh C et al: "Regulation of cystic fibrosis transmembrane conductance regulator (CFTR) gene transcription and alternative RNA splicing in a model of developing intestinal epithelium."

No. Sentence Comment

194 Furthermore, exon9 is the site of twomissense mutations known to causeclinical CF (A455E and G458V), emphasizing the functional importanceof this portionof NBFl (41,42). Login to comment

PMID: 1378801 [PubMed] McIntosh I et al: "Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis."

No. Sentence Comment

109 CF mutations that occur at a frequency of 5% or greater in certain population groups Region Mutation Population group Frequency Reference Transmembrane 1-6 621 + 1GT 711+1GT French Canadian; Saguenay-Lac St. Jean French Canadian; Urban Quebec 0.23 0.09 72 72 NBF 1 A455E SF508 G542X G551D French Canadian; Saguenay-Lac St. Jean Worldwide Ashkenazi Jewish Spanish Scottish 0.08 0.30-0.88 0.12 0.05 0.05 72 14 73 74 75 Transmembrane 7-12 R1162X N.E. Italian 0.05 74 NBF 2 W1282X Ashkenazi Jewish 0.48 56, 73 press CFTR and in those used for transient expression studies (33). Login to comment

PMID: 1376017 [PubMed] Cutting GR et al: "Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians."

No. Sentence Comment

148 This phenomenon also appears to account for the high frequency of mutations 621 + 1G-*T and A455E observed in French-Canadian families from the Saguenay-Lac St. Jean region ofQuebec (Rozen et al. 1992). Login to comment

PMID: 1376016 [PubMed] Kristidis P et al: "Genetic determination of exocrine pancreatic function in cystic fibrosis."

No. Sentence Comment

10 This result is thus consistent with the hypothesis that PI and PS in CF are predisposed by the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as AF508, A1507, Q493X, G542X, R553X, W1282X, 621 + 1G-PT, 1717-1G--'A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T. Login to comment
57 Intron 4: 621 + 1G-T Exon 7: R334W ......... R347P ........... Exon 9: A455E .......... G458V .......... G480C .......... Exon 10: Q493X .......... A1507 ........... AF508 .......... VS2OF .......... Login to comment
66 As shown in table 3, meconium ileus Table 2 1181 Table 3 Frequency of 25 CF Mutations in Chromosomes of the Toronto Study Population Mutation AF508 ...... G551D...... G542X...... 621 +1G-'T N1303K..... W1282X..... R1 17H...... 1717-1G-~A R560T...... A1507 ...... R553X...... V52OF ...... R334W ..... A455E...... I148T ...... Q493X...... P574H...... R347P ...... SS6delA ..... 3659delC .... G480C...... 444delA ..... D110H...... G458V...... S549R ...... Y563N...... Login to comment
81 Table 4 Classification of CF Gene Mutations as Severe or Mild with Respect to Pancreatic Function Type of Mutation Severe (location) Mild (location) Missense (point mutation) ...... 1148T (exon 4) R117H (exon 4) G480C (exon 9) R334W (exon 7) VS2OF (exon 10) GSS1D (exon 11) R347P (exon 7) RS60T (exon 11) A455E (exon 9) N1303K (exon 21) P574H (exon 12) Single amino acid deletion ........ AFS08 (exon 10) A1507 (exon 10) Stop codon (nonsense) ..... Q493X (exon 10) G542X (exon 11) R553X (exon 11) W1282X (exon 20) Splice junction ... 621 + 1G-T (intron 4) 1717-1G-T (intron 10) Frameshift ........ 556delA (exon 4) 3659delC (exon 19) with any of the mild mutations was associated with PS. Login to comment
85 Accordingly, the mutations R117H, R334W, R347P, A455E, and P574H may be regarded as mild, whereas AF508, AI507, Q493X, G542X, R553X, W1282X, 621 + 1G-T, 1717-1G--A, 556delA, 3659delC, 1148T, G480C, V520F, GSS1D, and R560T are severe. Login to comment

PMID: 1284470 [PubMed] Tucker SJ et al: "Identification and developmental expression of the Xenopus laevis cystic fibrosis transmembrane conductance regulator gene."

No. Sentence Comment

115 Other missense mutations implicated in the disease, A455E and G458V (25)(26), also show conservation at these positions, supporting the view that they are functionally important. Login to comment

PMID: 1371263 [PubMed] Dork T et al: "Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families."

No. Sentence Comment

25 Most CFTR mutations were investigated by restriction analysis of PCR products (R334W, R347P, A455E, G551D, R553X, 2789+5 G---~A,Rl162X, W1282X) (Cutting et al. 1990; Dean et al. 1990b; Gasparini et al. 1991b; Highsmith et al. 1990; Kerem et al. 1990;Vidaud et al. 1990) (see Table 4). Login to comment
98 ASO, Allele-specificoligonucleotide hybridization; TGGE, temperature gradient gel electrophoresis; SSCP, single strand conformation polymorphism Mutation Localization No. % Method of detectiona Reference R117H Exon 4 2 0.4 ASO Dean et al. (1990b) R334W Exon 7 2 0.4 RFLP MspI Gasparini et al. (1991b) R347P Exon 7 5 1.0 RFLP NcoI Dean et al. (1990b) A455E Exon 9 1 0.2 RFLP AciI Kerem et al. (1990) F508C2 Exon 10 1 0.2 Nondenaturing PAGE Kobayashi et al. (1990) AF508 Exon 10 370 74.0 Nondenaturing PAGE Kerem et al. (1989) 1717-1 G---~A Intron 10 2 0.4 TGGE Kerem et al. (1990) G542X Exon 11 5 1.0 Allele-specificPCR Kerem et al. (1990) G551D Exon 11 5 1.0 RFLP DpnII Cutting et al. (1990) R553X Exon 11 12 2.4 RFLP HincII Cutting et al. (1990) 2789 + 5 G---~A Intron 14B 3 0.6 RFLP SspI Highsmith et al. (1990) Rl162X Exon 19 1 0.2 RFLP DdeI Gasparini et al. (1991b) 3659delC Exon 19 3 0.6 SSCP Kerem et al. (1990) W1282X Exon 20 2 0.4 RFLP MnlI Vidaud et al. (1990) N1303K Exon 21 7 1.4 Allele-specificPCR Osborne et al. (1991) Unpublished 13 2.6 Unknown 66 13.2 Total 500 a All non-AF508 mutations were subsequently verified by direct genomic sequencing of the respective PCR product b F508C was first detected on an N chromosome (Kobayashi et al. 1990) and hence is suspected to represent a benign missense mutation Table 5. Login to comment
100 The four major haplotypes are indicated in bold type KM.19 D9 J44 GATT TUB9 M470V T854T TUB18 TUB20 Mutation 1 l 2 1 2 2 1 1 2 2 2 1 1 2 1 2 2 1 2 2 1 1 2 1 2 1 2 2 2 1 2 1 1 1 1 2 2 2 1 2 1 1 1 2 i 1 2 1 2 1 1 2 1 2 R347P, F508C, R1162X, 3659delC 1717-1 G--~A, G551D, R553X (n = 2), 2789 + 5 G---~A,W1282X R117H R334W, A455E, G542X, N1303K, AF508 (96%) ~F508 (4%) R553X (n = 10) a Haplotypes were assigned from the individual pedigrees mutation was located on a single KM. 19-D9-J44-GATT-TUB9-M470V-T854T haplotype. Login to comment
106 Several more frequent disease-causing sequence variations, such as R334W, A455E, G542X, and N1303K, reside on the typical AF508 haplotype. Login to comment
134 1) A455E, G551D, 3659delC, W1282X, and N1303K were first detected on chromosomes of Anglo-Saxon or French origin (Cutting et al. 1990; Kerem et al. 1990; Vidaud et al. 1990; Osborne et al. 1991). Login to comment

PMID: 10762539 [PubMed] Mickle JE et al: "Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels."

No. Sentence Comment

37 Specifically, two missense mutations in NBF1 have been evaluated: A455E, which is associated with mild lung disease, and G551D, which is associated with a more severe pulmonary phenotype (Hamosh et al. 1992; Gan et al. 1995). Login to comment
38 CFTR bearing A455E retains both CFTR Cl2 channel activity and the ability to regulate ORCCs (Fulmer et al. 1995). Login to comment
47 DNA was assayed for 16 common CFTR mutations (R117H, 62111GrT, R334W, R349P, A455E, DI507, DF508, 1717-1GrA, G542X, S549N, G551D, R553X, R560T, 3849110 Kb CrT, W1282X, and N1303K), by reverse dot-blot hybridization (Mickle et al. 1998). Login to comment
182 d Data for A455E and G551D have been reported elsewhere (Fulmer et al. 1995). Login to comment

PMID: 10931414 [PubMed] Massie RJ et al: "Pancreatic function and extended mutation analysis in DeltaF508 heterozygous infants with an elevated immunoreactive trypsinogen but normal sweat electrolyte levels."

No. Sentence Comment

26 Measurement of Cl levels was done by colorimetry, and measurement of sodium levels was done by flame cytometry.16 Gene Mutation Analysis Blood was taken and DNA extract- ed17 for an extended cystic fibrosis transmembrane conductance regulator protein gene mutation analysis as described previously.18 The following mutations were included: ࢞F508, ࢞I507, R117H, G551D, A455E, G542X, N1303K, W1282X, 1717-1G࢐A, R560T, R347P, R334W, R553X, R1162X, S549N, 3849+10C࢐T, and 621+1G࢐T. Login to comment

PMID: 11755047 [PubMed] Gomez-Llorente MA et al: "Analysis of 31 CFTR mutations in 55 families from the South of Spain."

No. Sentence Comment

31 T I.19 A455E E.9 3849 + 4A ! Login to comment

PMID: 11755605 [PubMed] Hamilton JW et al: "Gentamicin in pharmacogenetic approach to treatment of cystic fibrosis."

No. Sentence Comment

75 THE LANCET ߦ Vol 358 ߦ December 15, 2001 2015 COMMENTARY Effect of CFTR mutations in epithelial cells Lumen Cytoplasm Nucleus Class 4 (eg, R117H) Class 3 (eg, G551D) Class 2 (eg, èc;F508) Class 1 (eg, G542X) Class 5 (eg, A455E) Apical surface Basolateral surface ATP CFTR MSD NBD NBD RD Golgi ER CFTR gene Collectively, the five mutant classes result in little or no functional CFTR expression at the apical surface of epithelial cells, but through different mechanisms. Login to comment
81 Class 5 mutations (such as A455E) reduce synthesis by impairing transcription, causing alternative splicing of mRNA, or causing aminoacid substitutions that alter early steps in protein biogenesis. Login to comment

PMID: 12767731 [PubMed] McKone EF et al: "Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study."

No. Sentence Comment

9 èc;F508/R117H, èc;F508/èc;I507, èc;F508/ 3849+10 kbC࢐T, èc;F508/2789+5G࢐A, and èc;F508/A455E have a milder clinical phenotype. Login to comment
47 ARTICLES 1672 THE LANCET ߦ Vol 361 ߦ May 17, 2003 ߦ www.thelancet.com Panel 1: Frequencies of CFTR mutations* CFTR Allele CFTR Allele mutation frequency (%) mutation frequency èc;F508 69&#b7;4% 2789+5G࢐A 0&#b7;3% Unknown 15&#b7;7% R1162X 0&#b7;3% G542X 2&#b7;3% G85E 0&#b7;3% G551D 2&#b7;2% R560T 0&#b7;2% èc;I507 1&#b7;6% R334W 0&#b7;2% W1282X 1&#b7;4% 3659èc;C 0&#b7;2% N1303K 1&#b7;2% A455E 0&#b7;1% R553X 0&#b7;9% 711+1G࢐T 0&#b7;1% 621+1G࢐T 0&#b7;8% 1898+1G࢐A 0&#b7;1% R117H 0&#b7;7% 2184èc;A 0&#b7;1% 3849+10 kbC࢐T 0&#b7;7% S549N 0&#b7;1% 1717-IG࢐A 0&#b7;5% 1078èc;T 0&#b7;03% R347P 0&#b7;3% *n=17 853. Login to comment
48 Panel 2: Functional classification of CFTR alleles Class Functional effect of Allele mutation I Defective protein G542X, R553X, W1282X, production R1162X, 621-1G࢐T, 1717-1G࢐A, 1078èc;T, 3659èc;C II Defective protein èc;F508, èc;I507, N1303K, processing S549N III Defective protein G551D, R560T regulation IV Defective protein R117H, R334W, G85E, conductance R347P V Reduced amounts of 3849+10KbC࢐T, functioning CFTR protein 2789+5G࢐A, A455E Unknown 711+1G࢐T, 2184DA, 1898+1G࢐A Total cohort Genotyped cohort (n=28 455) (n=17 853) Person-years at risk 152 011 96 870 Sex (% male) 53% 52% Race (% white) 96% 96% Age (years) 11&#b7;9 (11&#b7;1) 10&#b7;9 (11&#b7;2) Age at diagnosis (years) 3&#b7;5 (7&#b7;1) 3&#b7;6 (7&#b7;5) Sweat test (mmol/L) 101 (19) 100 (20) FEV1 (L) 1&#b7;72 (0&#b7;91) 1&#b7;80 (0&#b7;92) FEV1 (% predicted) 69 (29) 72 (28) FVC (L) 2&#b7;41 (1&#b7;18) 2&#b7;50 (1&#b7;21) FVC (% predicted) 81% (28) 84% (24) Height (cm) 121% (41) 117% (41) Weight (kg) 30&#b7;0 (21&#b7;3) 28&#b7;6 (21&#b7;8) Pancreatic insufficiency (%) 90% 87% P aeruginosa colonisation (%) 49% 46% Number of deaths (%) 3548 (12%) 1547 (9%) Data are mean (SD) unless otherwise stated. Login to comment
67 Table 2: Standardised and crude mortality rates (including organ transplantation) by genotype Genotype No of Age at Sweat FEV1 FVC Height Weight Pancreatic P&#b7; aeruginosa Subjects Diagnosis Chloride (% predicted)* (% predicted)* (cms)* (kg)* Insufficiency Colonization (yrs) (mmol) (%)ߤ (%)ߤ èc;F508/èc;F508 6 213 2&#b7;5 &#b1; 0&#b7;1 104 &#b1; 0&#b7;2 77 &#b1; 0&#b7;3 89 &#b1; 0&#b7;3 141 &#b1; 0&#b7;2 37&#b7;0 &#b1; 0&#b7;1 92 (91-92) 60 (59-61) èc;F508/G551D 411 3&#b7;7 &#b1; 0&#b7;3ߥ 108 &#b1; 0&#b7;9ߥ 76 &#b1; 1&#b7;2 89 &#b1; 1&#b7;2 142 &#b1; 0&#b7;7&#a7; 38&#b7;2 &#b1; 0&#b7;6&#a7; 92 (89-94) 59 (54-64) èc;F508/G542X 389 1&#b7;9 &#b1; 0&#b7;2 104 &#b1; 0&#b7;8 79 &#b1; 1&#b7;2 91 &#b1; 1&#b7;2 141 &#b1; 0&#b7;7 37&#b7;3 &#b1; 0&#b7;5 93 (89-95) 57 (52-62) èc;F508/N1303K 213 2&#b7;1 &#b1; 0&#b7;3 106 &#b1; 1&#b7;2 80 &#b1; 1&#b7;8 91 &#b1; 1&#b7;7 141 &#b1; 1&#b7;0 37&#b7;1 &#b1; 0&#b7;6 92 (87-95) 61 (55--68) èc;F508/W1282X 205 1&#b7;6 &#b1; 0&#b7;2 103 &#b1; 1&#b7;2 80 &#b1; 1&#b7;7 92 &#b1; 1&#b7;6 141 &#b1; 0&#b7;9 37&#b7;4 &#b1; 0&#b7;7 94 (90-97) 59 (52-65) èc;F508/R553X 164 2&#b7;5 &#b1; 0&#b7;4 106 &#b1; 1&#b7;4 76 &#b1; 1&#b7;8 89 &#b1; 1&#b7;6 139 &#b1; 0&#b7;9 35&#b7;4 &#b1; 0&#b7;7&#a7; 90 (85-94) 60 (53-67) èc;F508/621-1G 162 2&#b7;5 &#b1; 0&#b7;4 107 &#b1; 1&#b7;3 78 &#b1; 1&#b7;8 89 &#b1; 1&#b7;5 143 &#b1; 1&#b7;0&#a7; 38&#b7;8 &#b1; 0&#b7;8&#a7; 87 (80-91)&#a7; 57 (49-64) èc;F508/èc;I507 149 8&#b7;5 &#b1; 1&#b7;1ߥ 95 &#b1; 1&#b7;9ߥ 86 &#b1; 2&#b7;1ߥ 93 &#b1; 1&#b7;8&#a7; 137 &#b1; 1&#b7;4&#a7; 37&#b7;4 &#b1; 1&#b7;25 84 (78-89)ߥ 39 (31-48)ߥ èc;F508/R117H 123 13&#b7;7 &#b1; 1&#b7;2ߥ 80 &#b1; 1&#b7;9ߥ 91 &#b1; 2&#b7;1ߥ 97 &#b1; 1&#b7;7ߥ 143 &#b1; 1&#b7;8 42&#b7;9 &#b1; 1&#b7;7ߥ 65 (55-73)ߥ 22 (16-29)ߥ èc;F508/3849+10 kB 114 11&#b7;3 &#b1; 0&#b7;9ߥ 72 &#b1; 2&#b7;5ߥ 77 &#b1; 2&#b7;1 87 &#b1; 1&#b7;9 144 &#b1; 1&#b7;4&#a7; 41&#b7;2 &#b1; 1&#b7;2ߥ 66 (57-74)ߥ 69 (59-77) èc;F508/2789+5G 63 13&#b7;4 &#b1; 1&#b7;6ߥ 102 &#b1; 2&#b7;1 88 &#b1; 2&#b7;8ߥ 97 &#b1; 2&#b7;3ߥ 140 &#b1; 2&#b7;5 41&#b7;8 &#b1; 2&#b7;2&#a7; 71 (59-81)ߥ 32 (22-44)ߥ èc;F508/1717-1G 74 1&#b7;3 &#b1; 0&#b7;3 103 &#b1; 2&#b7;0 75 &#b1; 2&#b7;7 86 &#b1; 2&#b7;4 139 &#b1; 1&#b7;5 35&#b7;7 &#b1; 0&#b7;9 96 (88-99) 59 (48-69) èc;F508/R560T 46 1&#b7;7 &#b1; 0&#b7;5 104 &#b1; 2&#b7;0 84 &#b1; 3&#b7;3ߥ 96&#b1; 2&#b7;8&#a7; 142 &#b1; 1&#b7;9 38&#b7;4 &#b1; 1&#b7;4 91 (79-97) 63 (48-75) èc;F508/R347P 44 5&#b7;9 &#b1; 1&#b7;1&#a7; 105 &#b1; 2&#b7;6 76 &#b1; 3&#b7;0 90 &#b1; 2&#b7;9 142 &#b1; 2&#b7;4 38&#b7;7 &#b1; 1&#b7;8 67 (52-79)ߥ 53 (38-68) èc;F508/G85E 43 9&#b7;2 &#b1; 1&#b7;8ߥ 99 &#b1; 2&#b7;3&#a7; 76 &#b1; 2&#b7;5 90 &#b1; 2&#b7;5 142 &#b1; 2&#b7;9 38&#b7;3 &#b1; 2&#b7;2 88 (75-95) 52 (35-68) èc;F508/3659DC 40 1&#b7;1 &#b1; 0&#b7;4 105 &#b1; 2&#b7;1 76 &#b1; 3&#b7;9 88 &#b1; 4&#b7;1 139 &#b1; 1&#b7;9 36&#b7;6 &#b1; 1&#b7;2 92 (77-97) 55 (39-69) èc;F508/A455E 29 14&#b7;3 &#b1; 2&#b7;0ߥ 89 &#b1; 3&#b7;1ߥ 98 &#b1; 4&#b7;0ߥ 104 &#b1; 3&#b7;4ߥ 138 &#b1; 3&#b7;4 42&#b7;1 &#b1; 2&#b7;5&#a7; 60 (41--76)ߥ 17 (8-32)ߥ èc;F508/R334W 28 13&#b7;2 &#b1; 3&#b7;0ߥ 104 &#b1; 3&#b7;2 86 &#b1; 3&#b7;4&#a7; 94 &#b1; 3&#b7;3 138 &#b1; 3&#b7;2 42&#b7;3 &#b1; 3&#b7;5 67 (46-82)ߥ 51 (32--70) èc;F508/R1162X 26 1&#b7;9 &#b1; 1&#b7;1 101 &#b1; 2&#b7;3 77 &#b1; 4&#b7;2 92 &#b1; 4&#b7;6 138 &#b1; 1&#b7;8 36&#b7;5 &#b1; 1&#b7;4 92 (75-98) 65 (47-80) èc;F508/1898+1G 20 1&#b7;2 &#b1; 0&#b7;3 99 &#b1; 2&#b7;8 83 &#b1; 4&#b7;1 94 &#b1; 4&#b7;4 138 &#b1; 3&#b7;3 35&#b7;1 &#b1; 2&#b7;1 85 (61--95) 63 (39-82) èc;F508/2184DA 20 2&#b7;3 &#b1; 0&#b7;9 106 &#b1; 5&#b7;3 82 &#b1; 4&#b7;3 92 &#b1; 4&#b7;4 141 &#b1; 3&#b7;0 36&#b7;5 &#b1; 1&#b7;5 94 (69-99) 60 (38-79) èc;F508/711+1G 17 1&#b7;3 &#b1; 0&#b7;5 108 &#b1; 4&#b7;6 83 &#b1; 4&#b7;2 94 &#b1; 4&#b7;4 137 &#b1; 3&#b7;4 36&#b7;7 &#b1; 2&#b7;9 100 73 (50-88) èc;F508/S549N 11 6&#b7;4 &#b1; 1&#b7;9&#a7; 109 &#b1; 5&#b7;7 67 &#b1; 6&#b7;1 77 &#b1; 7&#b7;2 140 &#b1; 3&#b7;2 36&#b7;7 &#b1; 2&#b7;6 92 (62-99) 71 (40--90) èc;F508/Other 2 262 5&#b7;8 &#b1; 0&#b7;2ߥ 99 &#b1; 0&#b7;4ߥ 80 &#b1; 0&#b7;5ߥ 91 &#b1; 0&#b7;5ߥ 141 &#b1; 0&#b7;3 38&#b7;1 &#b1; 0&#b7;3ߥ 86 (84-87)ߥ 50 (48-52)ߥ Other/Other 1 551 7&#b7;5 &#b1; 0&#b7;3ߥ 93 &#b1; 0&#b7;6ߥ 82 &#b1; 0&#b7;6ߥ 90 &#b1; 0&#b7;6&#a7; 141 &#b1; 0&#b7;4 38&#b7;3 &#b1; 0&#b7;3ߥ 81 (80-84)ߥ 40 (38-43)ߥ Data are mean (SE) unless otherwise indicated. Login to comment
74 Patients with genotypes èc;F508/ R117H, èc;F508/A455E, èc;F508/èc;I507 and èc;F508/ 2789+5G࢐A had significantly better lung function and lower rates of P aeruginosa colonisation than èc;F508 homozygotes. Login to comment
106 Our work confirms previous findings that èc;F508/R117H,9 èc;F508/A455E,12 èc;F508/3849+10 kbC࢐T,13,25 and èc;F508/2789+5G࢐A13,25 are associated with mild clinical manifestations. Login to comment
123 The frequency of èc;F508 homozygotes and heterozygotes is similar to that of Kerem and co-workers.6 Rates of pancreatic insufficiency in the cohorts with èc;F508/R117H and èc;F508/A455E genotypes are higher than that recorded by others.9,12,27 This finding is probably related to an overestimation of pancreatic insufficiency from use of a surrogate marker- pancreatic enzyme supplementation. Login to comment

PMID: 1372093 [PubMed] Cuppens H et al: "Simultaneous screening for 11 mutations in the cystic fibrosis transmembrane conductance regulator gene by multiplex amplification and reverse dot-blot."

No. Sentence Comment

35 Mutation Number of CF chromosomes with the mutation Reference AF508 138(71-1%) 3 G542X 11 (5 .7%) 9 N1303K 6(3-1%) 15 1717-1G--*A 5 (2.6%) 8, 9 A455E 2 (1 .0%) 9 W1282X 2 (1 .0%) 10 G458V 1 (0.5%) 4 A1507 1 (0.5%) 9 Unidentified 28 (14.4%) cation was carried out on a DNA Thermal Cycler (Perkin Elmer-Cetus Instruments) . Login to comment
97 621 + IG-T A455E G458V A1507 AF508 1717-IG - A G542X G551D R553X WI282X N 1303 K 621+IG- .T A455E G458V A1507 AF508 1717-I G-> A G542X G551D R553X W1282X N1303K Fig. 2. Login to comment
100 Hybridization of pooled PCR products containing the mutant type alleles, obtained by amplification with mutant oligonucleotide probes, for the 621 +1G-+T, A455E, 1717-1G-+A mutations (F), the G458V, R553X, W1282X mutations (G) and the A1507, C551 D mutations (H) . Login to comment
101 A E M W Non-radioactive CF reverse dot-blot 37 B F M W C M W D M W G H 621 + IGT A455E G458V A1507 A F508 1717-IGA G542X G551D R553 X W1282X N1303K 621+IG-ߦT A455E G458V L 1507 AF508 1717-IG- A G542 X G551D R553X W1282X N 1303 K A F M W G B M W C H M W D M W E J M W Fig. 3. Login to comment

PMID: 15298139 [PubMed] Lewis MJ et al: "Cystic fibrosis."

No. Sentence Comment

95 ēa; ēa;Table 3ēa; ēa; Recommended Mutation Panel for Cystic Fibrosis Carrier Screening ࢞F508 ࢞I507 G542X G551D W1282X N1303K R553X 621+1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711+1G>T 1898+1G>A 2184delA 1078delT 3849+10kbC>T 2789+5G>A 3659delC I148T 3120+1G>A I506V* I507V* F508C* 5T/7T/9T* * Reflex tests. Login to comment

PMID: 15463806 [PubMed] Vankeerberghen A et al: "The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions."

No. Sentence Comment

241 The CFTR sequences essential for Cl transport and activation of y ORCC seem to be different: A455E and G551D are two CFTR mutations resulting in CFTR channels with reduced chloride transport but A455E retains its ability to stimulate ORCC and not G551d. Login to comment
242 A455E is associated with mild lung disease, G551D with severe, pointing to the importance of the regulatory properties of CFTR w103x. Login to comment
390 Mutations that cause a small defect in maturation but normal or increased chloride transport activity, like A455E and P574H tend to be classified in this fifth class of mutations w162x. Login to comment
394 Mutational analysis showed that two CFTR mutations resulting in CFTR channels with reduced chloride transport, A455E and G551D, have a different impact on the regulation of ORCC: A455E retains its ability to stimulate ORCC and G551D not w103x. Login to comment

PMID: 15463882 [PubMed] Hubert D et al: "Diagnosis of cystic fibrosis in adults with diffuse bronchiectasis."

No. Sentence Comment

47 We used an oligonucleotide ligation assay using a commercially available kit (Cystic Fibrosis Assay, Applied Biosystems, Foster City, CA, USA) to seek 31 mutations in the CFTR gene (F508del, I507del, Q943X, V520F, 1717y1GࡊA, G542X, G551D, R553X, R560T, S549R, S549 N, 3849q10kbCࡊT, 3849q4AࡊG, R1162X, 3659delC, W1282X, 3905insT, 621q1GࡊT, R117H, Y122X, 711q1GࡊT, 1078delT, R347P, R347H, R334 W, A455E, N1303K, G85E, 1898q1GࡊA, 2183AAࡊG, 2789q5GࡊA) which allowed to detect 82% of the CF alleles in France. Login to comment
129 * 31 mutations: F508del, I507del, Q493X, V520F, 1717y1GࡊA, G542X, G551D, R553X, R560T, S549R, S549 N, 3849q10kbCࡊT, 3849q ** 4AࡊG, R1162X, 3659delC, W1282X, 3905insT, 621q1GࡊT, R117H, Y122X, 711q1GࡊT, 1078delT, R347P, R347H, R334 W, A455E, N1303K, G85E, 1898q1GࡊA, 2183AAࡊG, 2789q5GࡊA. that the laboratory criteria for the diagnosis of CF should be expanded to include identification of CFTR mutations and abnormal bioelectrical properties of the nasal epithelium, in addition to the sweat test w7x. Login to comment
149 The next most frequent mutations were the 2183AAࡊG, 3849q10kbCࡊT, 3272y26AࡊG, A455E and 2789q5GࡊA mutations, which were all found in at least three patients. Login to comment
150 The 3849q10kbCࡊT, 3272y26A)G, A455E and 2789q 5GࡊA mutations belong to the class V of CFTR mutations, which result in residual levels of CFTR transcripts and protein w17,24x. Login to comment
151 The A455E missense mutation is associated with mild lung disease w27x, whereas the 3272y26AࡊG w28x, 2789q5GࡊA w29x and 3849q10kbCࡊT w22x mutations are associated with a milder CF phenotype. Login to comment

PMID: 16635477 [PubMed] Lucarelli M et al: "A 96-well formatted method for exon and exon/intron boundary full sequencing of the CFTR gene."

No. Sentence Comment

26 None of these subjects showed any clinical manifestations of CF, nor were any positive for CFTR mutations when analyzed by means of the PCR/OLA/SCS method (Celera Diagnostics) [21], which searches for the most common worldwide 31 CFTR mutations (G85E, R117H, Y122X, 621+1G->T, 711+1G->T, 1078delT, R347P, R347H, R334W, A455E, DF508, DI507, Q493X, V520F, 1717-1G->A, G542X, G551D, R553X, R560T, S549R(T->G), S549N, 1898+1G->A, 2183AA->G, 2789+5G->A, R1162X, 3659delC, 3849+10kbC->T, 3849+4A->G, W1282X, 3905insT, N1303K), including the 12 most common in Italy [1,22]. Login to comment

PMID: 16963320 [PubMed] Perez MM et al: "CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent."

No. Sentence Comment

78 At least another 38 mutations have been searched for, but none of them were found in the CF patients from Latin America: p.E60X, p.Y122X, p.G178R, p.G330X, p.R347H, p.R352Q, p.S364P, p.A455E, p.Q493X, p.V520F, p.C524X, p.R560T, p.Y563D, p.P574H, p.K710X, p.Q890X, p. R1158X, p.S1196X, p.S1255X, p.D1270N, p.W1310X, p. W1316X, c.405+1G-A, c.444delA, c.556delA, c.574delA, c.1677delTA, c.2043delG, c.2307insA, c.2909delT, c.3120G-A, c.3358delAC, c.3662delA, c.3750delAG, c.3791delC, c.3821delT, c.3849+4A-G, c.3905insT. Login to comment

PMID: 19181498 [PubMed] Gaillard D et al: "[Mild cystic fibrosis: genetics - extending follow-up is necessary]."

No. Sentence Comment

43 Parmi les variations de s&#e9;quence identifi&#e9;es en p&#e9;riode n&#e9;onatale par le kit &#c9;lucig&#e8;ne1 CF30, plusieurs sont reconnues comme ayant un effet mod&#e9;r&#e9;, comme R117H, R334W, R2789 + 5G > A, 3272-26A > G, 3849 + 10kbC > T [7,9,10], voire variable, notamment G85E, A455E [3] ; les 23 autres mutations sont reconnues comme s&#e9;v&#e8;res. Login to comment

PMID: 20166764 [PubMed] Becq F et al: "Cystic fibrosis transmembrane conductance regulator modulators for personalized drug treatment of cystic fibrosis: progress to date."

No. Sentence Comment

105 [38] Class V mutations (e.g. A455E, P574H) are responsible for the production of functional proteins with normal Cl-channel activity and regulation, but at a reduced rate of synthesis. Login to comment

PMID: 20619026 [PubMed] Ras JE et al: "[Cystic fibrosis in a woman aged seventy]."

No. Sentence Comment

63 TABEL 1 Classificatie van mutaties in het 'cystic fibrosis transmembrane conductance regulator`(CFTR)-gen op chromosoom 7 klasse mechanisme enkele bekende mutaties I geen synthese van het CFTR-eiwit G542X R553X W1282X R1162X 621-1G࢐T 1717-1G࢐A 1078࢞T 3659࢞C II defect in eiwitrijping met voortijdig afbraak ࢞F508 ࢞I507 N1303K S549N III verstoorde regulatie van de CFTR-functie G551D R56OT IV verstoorde conductie van chloride of verstoorde kanaalopening R117H R334W G85E R347P V minder synthese van het CFTR-eiwit 3849+10KbC࢐T 2789+5G࢐A A455E TABEL 2 Diagnostiek van cystische fibrose test testuitslag klassieke CF* niet-klassieke CFߤ zweettest chlorideconcentratie > 60 mmol/l chlorideconcentratie ࣘ 60 mmol/l neuspotentiaalmeting afwijkend niet-afwijkend CFTR-mutatie-analyse 2 mutaties 2 mutaties CF = cystische fibrose; CFTR = 'cystic fibrosis transporter regulator`-gen. Login to comment

PMID: 22043142 [PubMed] Lilley M et al: "Newborn screening for cystic fibrosis in Alberta: Two years of experience."

No. Sentence Comment

46 These include the following mutations: delF508, I507del, G542X, G85E, R117H, 621+1G࢐T, 711+1G࢐T, G551D, R334W, R347P, A455E, 1717-1G࢐A, R560T, R553X, N1303K, 1898+1G࢐A, 2184delA, 2789+5G࢐A, 3120+1G࢐A, R1162X, 3659delC, 3849+10kbC࢐T, W1282X, 1078delT, 394delTT, Y122X, R347H, V520F, A559T, S549N, S549R, 1898+5G࢐T, 2183AA࢐G, 2307insA, Y1092X, M1101K, S1255X, 3876delA and 3905insT. Login to comment

PMID: 23209179 [PubMed] Ferec C et al: "Assessing the Disease-Liability of Mutations in CFTR."

No. Sentence Comment

101 However, when a sufficiently large number of patients with identical genotypes are found in a single geographic location such as Belgium and in French Canada, a correlation with decline in lung function becomes evident for the A455E (p.Ala455Glu) mutation (Gan et al. 1995; De Braekeleer et al. 1997). Login to comment

PMID: 23317763 [PubMed] van Meegen MA et al: "CFTR-mutation specific applications of CFTR-directed monoclonal antibodies."

No. Sentence Comment

3 Mutant CFTR was detected in HEK293 cells transiently expressing the mutations; G542X, R1162X, F508del, N1303K, G551D, R117H, A455E. Login to comment
22 http://dx.doi.org/10.1016/j.jcf.2012.12.005 functional CFTR is observed for class V (A455E) and VI mutations, due to impaired biosynthesis and decreased stability of the CFTR protein, respectively [5,12]. Login to comment
23 However, many CFTR mutations cannot be strictly classified into single classes as was shown for A455E and F508del [12-14]. Login to comment
76 We selected wt-CFTR, F508del (class II), G542X (I), R1162X (I), G551D (III), R117H (IV), A455E (V), and N1303K (II) that were ectopically expressed in HEK293 cells. Login to comment
83 For class V mutant A455E, the majority of the protein was core-glycolysated band B and only limited complex-glycosylated CFTR (C-band) was observed. Login to comment
95 CFTR Mutants F508del R1162X G551D R117H A455E N1303K 596, 769, 24.1 , 570, 432,450 570, 432, 450 570, 432, 450, 24.1, 769, 596 570, 570, 596, 769, 24.1, 432, 450 596, 769, 24.1, 432, 450 769, 596, 570, 24.1, 432, 450 is likely still preserved and bound to interacting proteins that may affect the binding to specific mAbs. Login to comment
111 G551D was expressed at levels comparable to wt-CFTR, expression of R117H, N1303K, A455E and R1162X was intermediate, and low levels were observed for F508del and G542X. Login to comment
145 Western blots containing 25 bc;g of total protein of HEK293 cells transiently transfected with pcDNA3 containing; CFTR-wt, F508del, G542X, R1162X, G551D, R117H, A455E, N1303K or empty vector. Login to comment
152 Limited detection was observed for R1162X and A455E. Login to comment
155 Detection of CFTR was limited for F508del and A455E and CFTR mutants G542X and R1162X were not detectable. Login to comment
217 Interestingly, for mutant A455E we demonstrated CFTR protein levels slightly higher than mutant F508del, with comparable B-C ratio (quantification not shown), suggesting that trafficking is impaired as well. Login to comment
218 A455E is considered to be a mild mutation as it is associated with pancreas sufficiency (http://cftr2.org), indicating that the limited levels of A455E C-band have increased activity as compared to N1303K and F508del, as previously noted [33], or that some A455E B-band may have activity at the plasma membrane as has been described for F508del [34]. Login to comment
220 Furthermore, we provide more insight on the impact of CFTR mutations N1303K, A455E, G551D and R117H on CFTR expression. Login to comment

PMID: 23378603 [PubMed] Thauvin-Robinet C et al: "CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders."

No. Sentence Comment

125 (Ala455Glu);( Arg117His) p.Gly551Asp 1995 No spontaneous pregnancy and no in vitro fertilisation - CF or CFTR-RD p. Login to comment

PMID: 23457166 [PubMed] Derichs N et al: "Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis."

No. Sentence Comment

76 ASL hydration is achieved through establishment of an osmotic gradient by a predominant efflux of chloride ions through CFTR channels, coupled with a moderate influx of sodium ions through epithelial 100 80 60 40 20 0 Sweat chloride mmol&#b7;L -1 Sweat chloride in CF CFTR protein function % 20 0 40 60 80 100 >60 mmol&#b7;L-1 diagnostic cut-off for CF Normal Normal Carriers Carriers CF with pancreatic insufficiency Class I-III (F508del, G551D, W1282X) CF with pancreatic sufficiency Class IV-V (3849+10kbC-T, A455E) CBAVD with two CF mutations (R117H, 5T) CFTR-related disorder (pancreatitis, bronchiectasis, CBAVD) Adults ? Login to comment

PMID: 23483918 [PubMed] van Meegen MA et al: "Apical CFTR expression in human nasal epithelium correlates with lung disease in cystic fibrosis."

No. Sentence Comment

66 62% yes insufficient 3 F508del/A455E F 18. Login to comment
208 1717-1G.A Class I altered splicing 365insT Class I frameshift 4243-3T.A Class V altered splicing A455E Class II, V missense F508del Class II, III, VI amino acid deletion IVS11-1G.C Class I altered splicing R553X Class I nonsense S1252N Class III missense doi:10.1371/journal.pone.0057617.t003 Supporting Information Figure S1 Bland-Altman plots. Login to comment

PMID: 23724185 [PubMed] Farjadian S et al: "Clinical and genetic features in patients with cystic fibrosis in southwestern iran."

No. Sentence Comment

26 Genomic DNA was extracted from 200 &#b5;L of whole blood with the QiaAmp DNA Mini Kit (Qiagen, Valencia, CA, USA) and 29 common CFTR gene mutations (D1152H, 1717-1G>A, G542X, W1282X, N1303K, ࢞F508, 3849+10kbC>T, 394delTT, 621+1G>T, S1251N, G551D, R117H, R1162X, R334W, A455E, 2183AA>G, 3659delC, 1078delT, ࢞I507, R347P, R553X, E60X, 3120+1G>A, 2789+5G>A, 1898+1G>A, 711+1G>T, G85E, 2184delA and R560T) were analyzed with the ELUCIGENE CF29 v. 2 kit using four multiplex PCR. Login to comment

PMID: 23727931 [PubMed] Dekkers JF et al: "A functional CFTR assay using primary cystic fibrosis intestinal organoids."

No. Sentence Comment

127 (d) Forskolin-induced swelling of rectal organoids derived from three individual healthy controls, two individuals with a mild cystic fibrosis genotype (F508del A455E) and nine individuals with a severe cystic fibrosis genotype (one individual with E60X 4015ATTTdel, one with F508del G542X, one with F508del L927P and six with F508del F508del). Login to comment
140 We next compared the efficacy of approaches to restore the function of F508del CFTR by comparing the amount of FIS to that in mock-treated F508del A455E organoids or healthy control organoids (Fig. 5d). Login to comment
141 This comparison indicated that VX-809 is the most potent corrector and combined treatment with VX-809 and VX-770 induced FIS beyond the amounts in F508del A455E organoids, reaching ~60% of the FIS in healthy controls. Login to comment
150 0 500 1,000 1,500 2,000 2,500 0 500 1,000 1,500 2,000 2,500 3,000 0 400 800 1,200 1,600 C8 Corr-4a C8 + Corr-4a VX-809 VX-770 VX-809 + VX-770 VRT-325 Corr-4a VRT-325 + Corr-4a CF1 CF6 CF5 CF4 CF3 CF2 F508del L927P F508del G542X E60X 4015delATTT F508del F508del b d a c 0 20 40 60 80 100 120 V R T - 3 2 5 C o r r - 4 a C 8 V X - 8 0 9 V X - 7 7 0 V R T - 3 2 5 + C o r r - 4 a C 8 + C o r r - 4 a V X - 8 0 9 + V X - 7 7 0 C o n t r o l C o n t r o l F508del F508del HC F508del A455E Organoid swelling (absolute AUC t = 60) Organoid swelling (absolute AUC t = 60) Organoid swelling (absolute AUC t = 60) Organoid swelling (normalized AUC t = 60) Figure 5ߒ Differential FIS between organoids from subjects with cystic fibrosis after chemical CFTR restoration. Login to comment
154 (d) Average FIS responses of compound-treated F508del F508del organoids (n = 6 from a-c) and DMSO-treated F508del A455E organoids (n = 2) relative to the average FIS of DMSO-treated healthy control organoids (n = 3) expressed as the AUC calculated from the time periods shown in Figure 4d-f (baseline = 100%, t = 60 min; mean &#b1; s.e.m.). Login to comment
182 This combination induces approximately 1.5-fold more FIS in CFTR F508del homozygous organoids as compared to untreated F508del A455E organoids and up to 60% of the FIS seen in healthy controls. Login to comment

PMID: 23775370 [PubMed] Abou Tayoun AN et al: "A comprehensive assay for CFTR mutational analysis using next-generation sequencing."

No. Sentence Comment

53 of cases af9;/af9; c.1521_1523delCTT; c.1521_1523delCTT èc;F508; èc;F508 CF Yes 97 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.350Gb0e;A èc;F508; R117H CF Yes 53; 50 Dartmouth 1 af9;/af9; c.350Gb0e;A; c.1477Cb0e;T R117H; Q493*b CF Yes 52; 49 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.1000Cb0e;T èc;F508; R334W CF Yes 49; 54 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.489af9;1Gb0e;T èc;F508; 621af9;1Gb0e;T CF Yes 48; 47 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.1364Cb0e;A èc;F508; A455E CF Yes 51; 46 Dartmouth 1 af9;/af9; c.489af9;1Gb0e;T; c.2988af9;1Gb0e;A 621af9;1Gb0e;T; 3120af9;1Gb0e;A CF Yes 48; 49 Coriell 1 af9;/af9; c.1521_1523delCTT; c.1657Cb0e;T èc;F508; R553* CF Yes 44; 49c Coriell 2 af9;/af9; c.1521_1523delCTT; c.3528delC èc;F508; 3659delC CF Yes 46; 46 Coriell 1 af9;/af9; c.489af9;1Gb0e;T; c.579af9;1Gb0e;T 621af9;1Gb0e;T; 711af9;1Gb0e;T CF Yes 50; 51 Coriell 1 af9;/af9; c.489af9;1Gb0e;T; c.254Gb0e;A 621af9;1Gb0e;T; G85E CF Yes 50; 45 Coriell 1 af9;/af9; c.1521_1523delCTT; c.1679Gb0e;C èc;F508; R560T CF Yes 44; 52 Coriell 1 af9;/af9; c.489af9;1Gb0e;T; c.1364Cb0e;A 621af9;1Gb0e;T; A455E CF Yes 50; 49 Coriell 1 af9;/af9; c.3909Cb0e;G; c.4046Gb0e;A N1303K; G1349D CF Yes 47; 52 Coriell 1 af9;/af9; c.2657af9;5Gb0e;A; c.2657af9;5Gb0e;A 2789af9;5Gb0e;A; 2789af9;5Gb0e;A CF Yes 100 Coriell 1 af9;/af9; c.1040Gb0e;C; c.1652Gb0e;A R347P; G551D CF Yes 51; 49 Coriell 1 af9;/af9; c.1000Cb0e;T; c.3368-2Ab0e;T R334W; 3500-2Ab0e;G CF Yes 53; 45 Coriell 1 af9;/af9; c.254Gb0e;A; c.3454Gb0e;C G85E; D1152H CF Yes 44; 47 Coriell 1 af9;/af9; c.1521_1523delCTT; c.350Gb0e;A èc;F508; R117H CF Yes 49; 50 Coriell 1 af9;/af9; c.1521_1523delCTT; c.54-5940_273af9;10250del21kb èc;F508; CFTRdel2,3 CF Yes 47; N/Ad Coriell 1 af9;/af9; c.1521_1523delCTT; c.1766af9;1Gb0e;A èc;F508; 1898af9;1Gb0e;A CF Yes 47; 50 Coriell 1 af9;/af9; c.1521_1523delCTT; c.2051_2052delAAinsG èc;F508; K684Sfs CF Yes 47; 50 Coriell 1 af9;/af9; c.1521_1523delCTT; c.2052del èc;F508; K684Nfs*38 CF Yes 51; 55 Coriell 1 af9;/afa; c.1521_1523delCTT èc;F508 Carrier Yes 50c Dartmouth 16 af9;/afa; c.1652Gb0e;A G551D Carrier Yes 50c Dartmouth 5 af9;/afa; c.1519_1521delATC èc;I507 Carrier Yes 46 Dartmouth 1 af9;/afa; c.3454Gb0e;C D1152H Carrier Yes 50 Dartmouth 1 af9;/afa; c.1657Cb0e;T R553* Carrier Yes 51 Dartmouth 1 af9;/afa; c.178Gb0e;T E60* Carrier Yes 51 Dartmouth 1 af9;/afa; c.3846Gb0e;A W1282* Carrier Yes 45c Dartmouth 3 af9;/afa; c.1000Cb0e;T R334W Carrier Yes 51 Dartmouth 1 af9;/afa; c.1624Gb0e;T G542* Carrier Yes 47c Dartmouth 4 af9;/afa; c.3484Cb0e;T R1162* Carrier Yes 43 Dartmouth 1 af9;/afa; c.1766af9;1Gb0e;A 1898af9;1Gb0e;A Carrier Yes 57 Dartmouth 1 af9;/afa; c.3773_3774insT 3905insT (L1258Ffs*7) Carrier Yes 37 Dartmouth 1 af9;/afa; c.350Gb0e;A R117H Carrier Yes 50c Dartmouth 3 af9;/afa; c.1645Ab0e;C S549R Ab0e;C Carrier No N/A Dartmouth 1 af9;/afa; c.1040Gb0e;A R347H Carrier Yes 47 Dartmouth 1 af9;/afa; c.3909Cb0e;G N1303K Carrier Yes 46 Dartmouth 1 af9;/afa; c.3718-2477Cb0e;T 3849af9;10kbCb0e;T Carrier Yes 51 Coriell 1 af9;/afa; c.2988af9;1Gb0e;A 3120af9;1Gb0e;A Carrier Yes 49 Coriell 1 af9;/afa; c.489af9;1Gb0e;T 621af9;1Gb0e;T Carrier Yes 50 Coriell 1 af9;/afa; c.1585-1Gb0e;A 1717-1Gb0e;A Carrier Yes 51 Coriell 1 afa;/afa;e N/Af N/A Normal N/A N/A Dartmouth 9 a af9;/af9;, 2 pathogenic mutations; af9;/afa;, carrier of a single pathogenic mutation; afa;/afa;, absence of any pathogenic mutations. Login to comment
115 Mutation cDNA position Mutation class Sensitivity (TPa ) Specificity (TN) Accuracyb G85E c.254Gb0e;A Missense Detected (2/2) 100% (77/77) 100% R117H c.350Gb0e;A Missense Detected (6/6) 100% (73/73) 100% 621af9;1Gb0e;T c.489af9;1Gb0e;T Splice site Detected (6/6) 100% (73/73) 100% 711af9;1Gb0e;T c.579af9;1Gb0e;T Splice site Detected (1/1) 100% (78/78) 100% R334W c.1000Cb0e;T Missense Detected (3/3) 100% (76/76) 100% R347P c.1040Gb0e;C Missense Detected (1/1) 100% (78/78) 100% A455E c.1364Cb0e;A Missense Detected (2/2) 100% (77/77) 100% èc;I507 c.1519_1521delATC In-frame deletion Detected (1/1) 100% (78/78) 100% èc;F508 c.1521_1523delCTT In-frame deletion Detected (30/30) 100% (49/49) 100% G542* c.1624Gb0e;T Nonsense Detected (4/4) 100% (75/75) 100% G551D c.1652Gb0e;A Missense Detected (6/6) 100% (73/73) 100% R553* c.1657Cb0e;T Nonsense Detected (3/3) 100% (76/76) 100% R560T c.1679Gb0e;C Missense Detected (1/1) 100% (78/78) 100% 1898af9;1Gb0e;A c.1766af9;1Gb0e;A Splice site Detected (2/2) 100% (77/77) 100% 2789af9;5Gb0e;A c.2657af9;5Gb0e;A Splice site Detected (1/1) 100% (78/78) 100% 3120af9;1Gb0e;A c.2988af9;1Gb0e;A Splice site Detected (2/2) 100% (77/77) 100% R1162* c.3484Cb0e;T Nonsense Detected (1/1) 100% (78/78) 100% 3659delC c.3528del Frameshift deletion Detected (1/1) 100% (78/78) 100% 3849af9;10kbCb0e;T c.3718-2477Cb0e;T Splice site Detected (1/1) 100% (78/78) 100% W1282* c.3846Gb0e;A Nonsense Detected (3/3) 100% (75/75) 100% N1303K c.3909Cb0e;G Missense Detected (1/1) 100% (78/78) 100% 2184delA c.2052del Frameshift deletion Detected (1/1) 97% (76/78) 97% 1717-1Gb0e;A c.1585-1Gb0e;A Splice site Detected (1/1) 100% (78/78) 100% a TP, true-positive rate; TN, true-negative rate. Login to comment

PMID: 23866907 [PubMed] Landaburu I et al: "Genetic testing of sperm donors for cystic fibrosis and spinal muscular atrophy: evaluation of clinical utility."

No. Sentence Comment

51 The panel of mutations studied was: S549N, S549R, R553X, G551D, V520F, I507del, F508del, 3876delA, 1717-1G->A, G542X, R560T, 3120+1G->A, A455E, R117H, 394delTT, 2183AA- >G, 2184delA, 2789+5G->A, 1898+1G->A, 621+1G->T, 711+1G- >T, G85E, R347P, R347H, W1282X, R334W, 1078delT, 3849+10kbC->T, R1162X, N1303K, 3659delC, 3905insT. Login to comment

PMID: 23891399 [PubMed] Van Goor F et al: "Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function."

No. Sentence Comment

39 However, a significantly higher level (P b 0.05; ANOVA followed by Tukey's multiple comparisons test; n = 3-6) of mRNA expression was measured for P67L-, E92K-, and A455E-CFTR (Fig. 1). Login to comment
43 Mutations such as P67L-, E56K-, and A455E-CFTR exhibited intermediate levels of mature CFTR, which are consistent with less severe defects in CFTR processing (mature CFTR protein for P67L-, E56K-, and A455E-CFTR were 28.4&#b1; 6.8, 12.2&#b1;1.5, and 11.5&#b1;2.5% of normal, respectively). Login to comment
44 None M1V A46D E56K P67L R74W G85E E92K D110E D110H R117C R117H E193K L206W R334W I336K T338I S341P R347H R347P R352Q A455E L467P S492F F508del V520F A559T R560S R560T A561E Y569D D579G R668C L927P S945L S977F L997F F1052V H1054D K1060T L1065P R1066C R1066H R1066M A1067T R1070Q R1070W F1074L L1077P H1085R M1101K D1152H S1235R D1270N N1303K 0 100 200 300 400 500 600 * * * CFTR Mutation mRNA (% Normal CFTR) Fig. 1. Login to comment
64 Mutant CFTR form CFTR processing Mature/total % Normal CFTR Normal 0.89 &#b1; 0.01 100.0 &#b1; 18.5 G85E -0.05 &#b1; 0.04 -1.0 &#b1; 0.9 R560S 0.00 &#b1; 0.00 0.0 &#b1; 0.0 R1066C 0.02 &#b1; 0.01 0.0 &#b1; 0.0 S492F 0.00 &#b1; 0.00 0.1 &#b1; 0.1 R560T 0.01 &#b1; 0.01 0.2 &#b1; 0.1 V520F 0.05 &#b1; 0.03 0.3 &#b1; 0.2 M1101K 0.05 &#b1; 0.03 0.3 &#b1; 0.1 A561E 0.08 &#b1; 0.04 0.5 &#b1; 0.2 R1066M 0.02 &#b1; 0.02 0.5 &#b1; 0.4 N1303K 0.02 &#b1; 0.02 0.5 &#b1; 0.3 A559T 0.16 &#b1; 0.09 0.6 &#b1; 0.2 M1V 0.06 &#b1; 0.06 0.7 &#b1; 0.6 Y569D 0.11 &#b1; 0.04 0.6 &#b1; 0.2 R1066H 0.08 &#b1; 0.02a 0.7 &#b1; 0.2a L1065P 0.05 &#b1; 0.05 1.0 &#b1; 0.8 L467P 0.10 &#b1; 0.07 1.2 &#b1; 0.8 L1077P 0.08 &#b1; 0.04 1.5 &#b1; 0.6 A46D 0.21 &#b1; 0.08 1.9 &#b1; 0.5a E92K 0.06 &#b1; 0.05 1.9 &#b1; 1.3 H1054D 0.09 &#b1; 0.04 1.9 &#b1; 0.8 F508del 0.09 &#b1; 0.02a 2.3 &#b1; 0.5a H1085R 0.06 &#b1; 0.01a 3.0 &#b1; 0.7a I336K 0.42 &#b1; 0.05a 6.5 &#b1; 0.7a L206W 0.35 &#b1; 0.10a 6.8 &#b1; 1.7a F1074L 0.52 &#b1; 0.03a 10.9 &#b1; 0.6a A455E 0.26 &#b1; 0.10a 11.5 &#b1; 2.5a E56K 0.29 &#b1; 0.04a 12.2 &#b1; 1.5a R347P 0.48 &#b1; 0.04a 14.6 &#b1; 1.8a R1070W 0.61 &#b1; 0.04a 16.3 &#b1; 0.6a P67L 0.36 &#b1; 0.04a 28.4 &#b1; 6.8a R1070Q 0.90 &#b1; 0.01a 29.5 &#b1; 1.4a S977F 0.97 &#b1; 0.01a 37.3 &#b1; 2.4a A1067T 0.78 &#b1; 0.03a 38.6 &#b1; 6.1a D579G 0.72 &#b1; 0.02a 39.3 &#b1; 3.1a D1270N 1.00 &#b1; 0.00a,c 40.7 &#b1; 1.2a S945L 0.65 &#b1; 0.04a 42.4 &#b1; 8.9a L927P 0.89 &#b1; 0.01a,b 43.5 &#b1; 2.5a,b R117C 0.87 &#b1; 0.02a,b 49.1 &#b1; 2.9a,b T338I 0.93 &#b1; 0.03a,b 54.2 &#b1; 3.7a,b L997F 0.90 &#b1; 0.04a,b 59.8 &#b1; 10.4a,b D110H 0.97 &#b1; 0.01a,b 60.6 &#b1; 1.5a,b S341P 0.79 &#b1; 0.02a 65.0 &#b1; 4.9a,b R668C 0.94 &#b1; 0.03a,b 68.5 &#b1; 1.9a,b R74W 0.78 &#b1; 0.01a 69.0 &#b1; 2.7a,b D110E 0.92 &#b1; 0.05a,b 87.5 &#b1; 9.5a,b R334W 0.91 &#b1; 0.05a,b 97.6 &#b1; 10.0a,b K1060T 0.87 &#b1; 0.02a,b 109.9 &#b1; 28.0a,b R347H 0.96 &#b1; 0.02a,c 120.7 &#b1; 2.8a,b S1235R 0.96 &#b1; 0.00a,c 139.0 &#b1; 9.0a,b E193K 0.84 &#b1; 0.02a,b 143.0 &#b1; 17.1a,b R117H 0.86 &#b1; 0.01a,b 164.5 &#b1; 34.2a,b R352Q 0.98 &#b1; 0.01a,b 179.9 &#b1; 8.0a,c F1052V 0.90 &#b1; 0.01a,b 189.9 &#b1; 33.1a,b D1152H 0.96 &#b1; 0.02a,c 312.0 &#b1; 45.5a,b Notes to Table 1: Quantification of steady-state CFTR maturation expressed as the mean (&#b1;SEM; n = 5-9) ratio of mature CFTR to total CFTR (immature plus mature) or level of mature mutant CFTR relative to mature normal-CFTR (% normal CFTR) in FRT cells individually expressing CFTR mutations. Login to comment
74 Because the level of CFTR mRNA was similar across the panel of cell lines tested, the range in baseline activity and ivacaftor response likely reflects the severity of the functional defect and/or the 0 50 100 150 200 S341P R347P L467P S492F A559T A561E Y569D L1065P R1066C R1066M L1077P M1101K N1303K R560S L927P R560T H1085R V520F E92K M1V F508del H1054D I336K A46D G85E R334W T338I R1066H R352Q R117C L206W R347H S977F S945L A455E F1074L E56K P67L R1070W D110H D579G D110E R1070Q L997F A1067T E193K R117H R74W K1060T R668C D1270N D1152H S1235R F1052V Baseline With ivacaftor * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Chloride transport (% Normal) Mutant CFTR form 0 100 200 300 400 S341P R347P L467P S492F A559T A561E Y569D L1065P R1066C R1066M L1077P M1101K N1303K R560S L927P R560T H1085R V520F E92K M1V F508del H1054D I336K A46D G85E R334W T338I R1066H R352Q R117C L206W R347H S977F S945L A455E F1074L P67L E56K R1070W D110H D579G D110E R1070Q L997F A1067T E193K R117H R74W K1060T R668C D1270N D1152H S1235R F1052V * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Mature CFTR (% Normal) Mutant CFTR form A B Fig. 2. Login to comment
82 Mutation Patientsa Chloride transport (bc;A/cm2 ) Chloride transport (% normal) EC50 Baseline With ivacaftor Baseline With ivacaftor Fold increase over baselineb Normal 204.5 &#b1; 33.3 301.3 &#b1; 33.8c 100.0 &#b1; 16.3 147.3 &#b1; 16.5c 1.5 266 &#b1; 42 G551D 1282 1.5 &#b1; 0.7 113.2 &#b1; 13.0c 1.0 &#b1; 0.5 55.3 &#b1; 6.3c 55.3 312 &#b1; 73 F1052V 12 177.3 &#b1; 13.7 410.2 &#b1; 11.3c 86.7 &#b1; 6.7 200.7 &#b1; 5.6c 2.3 177 &#b1; 14 S1235R ND 160.6 &#b1; 25.7 352.1 &#b1; 43.4c 78.5 &#b1; 12.6 172.2 &#b1; 21.2c 2.2 282 &#b1; 104 D1152H 185 117.3 &#b1; 23.0 282.7 &#b1; 46.9c 57.4 &#b1; 11.2 138.2 &#b1; 22.9c 2.4 178 &#b1; 67 D1270N 32 109.5 &#b1; 20.5 209.5 &#b1; 27.4c 53.6 &#b1; 10.0 102.4 &#b1; 13.4c 1.9 254 &#b1; 56 R668C 45 99.0 &#b1; 9.4 217.6 &#b1; 11.7c 48.4 &#b1; 4.6 106.4 &#b1; 5.7c 2.2 517 &#b1; 105 K1060T ND 89.0 &#b1; 9.8 236.4 &#b1; 20.3c 43.5 &#b1; 4.8 115.6 &#b1; 9.9c 2.7 131 &#b1; 73 R74W 25 86.8 &#b1; 26.9 199.1 &#b1; 16.8c 42.5 &#b1; 13.2 97.3 &#b1; 8.2c 2.3 162 &#b1; 17 R117H 739 67.2 &#b1; 13.3 274.1 &#b1; 32.2c 32.9 &#b1; 6.5 134.0 &#b1; 15.7c 4.1 151 &#b1; 14 E193K ND 62.2 &#b1; 9.8 379.1 &#b1; 1.1c 30.4 &#b1; 4.8 185.4 &#b1; 1.0c 6.1 240 &#b1; 20 A1067T ND 55.9 &#b1; 3.2 164.0 &#b1; 9.7c 27.3 &#b1; 1.6 80.2 &#b1; 4.7c 2.9 317 &#b1; 214 L997F 27 43.7 &#b1; 3.2 145.5 &#b1; 4.0c 21.4 &#b1; 1.6 71.2 &#b1; 2.0c 3.3 162 &#b1; 12 R1070Q 15 42.0 &#b1; 0.8 67.3 &#b1; 2.9c 20.6 &#b1; 0.4 32.9 &#b1; 1.4c 1.6 164 &#b1; 20 D110E ND 23.3 &#b1; 4.7 96.4 &#b1; 15.6c 11.4 &#b1; 2.3 47.1 &#b1; 7.6c 4.1 213 &#b1; 51 D579G 21 21.5 &#b1; 4.1 192.0 &#b1; 18.5c 10.5 &#b1; 2.0 93.9 &#b1; 9.0c 8.9 239 &#b1; 48 D110H 30 18.5 &#b1; 2.2 116.7 &#b1; 11.3c 9.1 &#b1; 1.1 57.1 &#b1; 5.5c 6.2 249 &#b1; 59 R1070W 13 16.6 &#b1; 2.6 102.1 &#b1; 3.1c 8.1 &#b1; 1.3 49.9 &#b1; 1.5c 6.2 158 &#b1; 48 P67L 53 16.0 &#b1; 6.7 88.7 &#b1; 15.7c 7.8 &#b1; 3.3 43.4 &#b1; 7.7c 5.6 195 &#b1; 40 E56K ND 15.8 &#b1; 3.1 63.6 &#b1; 4.4c 7.7 &#b1; 1.5 31.1 &#b1; 2.2c 4.0 123 &#b1; 33 F1074L ND 14.0 &#b1; 3.4 43.5 &#b1; 5.4c 6.9 &#b1; 1.6 21.3 &#b1; 2.6c 3.1 141 &#b1; 19 A455E 120 12.9 &#b1; 2.6 36.4 &#b1; 2.5c 6.3 &#b1; 1.2 17.8 &#b1; 1.2c 2.8 170 &#b1; 44 S945L 63 12.3 &#b1; 3.9 154.9 &#b1; 47.6c 6.0 &#b1; 1.9 75.8 &#b1; 23.3c 12.6 181 &#b1; 36 S977F 9 11.3 &#b1; 6.2 42.5 &#b1; 19.1c 5.5 &#b1; 3.0 20.8 &#b1; 9.3c 3.8 283 &#b1; 36 R347H 65 10.9 &#b1; 3.3 106.3 &#b1; 7.6c 5.3 &#b1; 1.6 52.0 &#b1; 3.7c 9.8 280 &#b1; 35 L206W 81 10.3 &#b1; 1.7 36.4 &#b1; 2.8c 5.0 &#b1; 0.8 17.8 &#b1; 1.4c 3.6 101 &#b1; 13 R117C 61 5.8 &#b1; 1.5 33.7 &#b1; 7.8c 2.9 &#b1; 0.7 16.5 &#b1; 3.8c 5.7 380 &#b1; 136 R352Q 46 5.5 &#b1; 1.0 84.5 &#b1; 7.8c 2.7 &#b1; 0.5 41.3 &#b1; 3.8c 15.2 287 &#b1; 75 R1066H 29 3.0 &#b1; 0.3 8.0 &#b1; 0.8c 1.5 &#b1; 0.1 3.9 &#b1; 0.4c 2.6 390 &#b1; 179 T338I 54 2.9 &#b1; 0.8 16.1 &#b1; 2.4c 1.4 &#b1; 0.4 7.9 &#b1; 1.2c 5.6 334 &#b1; 38 R334W 150 2.6 &#b1; 0.5 10.0 &#b1; 1.4c 1.3 &#b1; 0.2 4.9 &#b1; 0.7c 3.8 259 &#b1; 103 G85E 262 1.6 &#b1; 1.0 1.5 &#b1; 1.2 0.8 &#b1; 0.5 0.7 &#b1; 0.6 NS NS A46D ND 2.0 &#b1; 0.6 1.1 &#b1; 1.1 1.0 &#b1; 0.3 0.5 &#b1; 0.6 NS NS I336K 29 1.8 &#b1; 0.2 7.4 &#b1; 0.1c 0.9 &#b1; 0.1 3.6 &#b1; 0.1c 4 735 &#b1; 204 H1054D ND 1.7 &#b1; 0.3 8.7 &#b1; 0.3c 0.8 &#b1; 0.1 4.2 &#b1; 0.1c 5.3 187 &#b1; 20 F508del 29,018 0.8 &#b1; 0.6 12.1 &#b1; 1.7c 0.4 &#b1; 0.3 5.9 &#b1; 0.8c 14.8 129 &#b1; 38 M1V 9 0.7 &#b1; 1.4 6.5 &#b1; 1.9c 0.4 &#b1; 0.7 3.2 &#b1; 0.9c 8.0 183 &#b1; 85 E92K 14 0.6 &#b1; 0.2 4.3 &#b1; 0.8c 0.3 &#b1; 0.1 2.1 &#b1; 0.4c 7.0 198 &#b1; 46 V520F 58 0.4 &#b1; 0.2 0.5 &#b1; 0.2 0.2 &#b1; 0.1 0.2 &#b1; 0.1 NS NS H1085R ND 0.3 &#b1; 0.2 2.1 &#b1; 0.4 0.2 &#b1; 0.1 1.0 &#b1; 0.2 NS NS R560T 180 0.3 &#b1; 0.3 0.5 &#b1; 0.5 0.1 &#b1; 0.1 0.2 &#b1; 0.2 NS NS L927P 15 0.2 &#b1; 0.1 10.7 &#b1; 1.7c 0.1 &#b1; 0.1 5.2 &#b1; 0.8c 52.0 313 &#b1; 66 R560S ND 0.0 &#b1; 0.1 -0.2 &#b1; 0.2 0.0 &#b1; 0.0 -0.1 &#b1; 0.1 NS NS N1303K 1161 0.0 &#b1; 0.0 1.7 &#b1; 0.3 0.0 &#b1; 0.0 0.8 &#b1; 0.2 NS NS M1101K 79 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS L1077P 42 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS R1066M ND 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS R1066C 100 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS L1065P 25 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS Y569D 9 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS A561E ND 0.0 &#b1; 0.1 0.0 &#b1; 0.1 0.0 &#b1; 0.0 0.0 &#b1; 0.1 NS NS A559T 43 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS S492F 16 0.0 &#b1; 0.0 1.7 &#b1; 1.2 0.0 &#b1; 0.0 0.8 &#b1; 0.6 NS NS L467P 16 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS R347P 214 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS S341P 9 0.0 &#b1; 0.0 0.2 &#b1; 0.2 0.0 &#b1; 0.0 0.1 &#b1; 0.1 NS NS a Number of individuals with the individual mutation in the CFTR-2 database (www.CFTR2.org). Login to comment
86 For example, the baseline level of chloride transport and ivacaftor response was higher for mutant CFTR forms associated with mild defects in CFTR processing (e.g., E56K, P67L, L206W, A455E, D579G, S945L, S977F, A1067T, R1070Q, R1070W, F1074L, and D1270N) than for those associated with severe defects in CFTR processing (e.g., F508del, H1054D, R1066H). Login to comment
92 Mutant CFTR forms that did not significantly respond to ivacaftor under the experimental conditions used in this study were generally associated with severe defects in CFTR processing A B C D E F 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 S1235R D1152H F1052V D1270N ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 R668C K1060T R74W R117H ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 E193K A1067T L997F R1070Q ivacaftor [Log M] Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 D110E D579G D110H R1070W ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 F1074L E56K P67L A455E ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 R347H S945L L206W S977F ivacaftor [Log M] 0 100 200 300 400 -8 -6 -4 0 T338I R1066H R117C R352Q ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 F508del R334W H1054D E92K ivacaftor [Log M] 0 5 10 15 20 -9 -8 -7 -6 -5 -4 0 F508del R334W H1054D E92K R1066H T338I ivacaftor [Log M] G H I Fig. 3. Login to comment

PMID: 24210900 [PubMed] Berkhout MC et al: "Sinonasal manifestations of cystic fibrosis: a correlation between genotype and phenotype?"

No. Sentence Comment

163 Genotype Frequency; N (%) Class of mutation F508del/F508del 61 (58.7) I-III F508del/3849 + 10kbC 2 (1.9) IV-V F508del/N1303K 2 (1.9) I-III F508del/R1162X 2 (1.9) I-III F508del/A455E 12 (11.5) IV-V F508del/3272-26A N G 5 (4.8) IV-V F508del/E528X 1 (1.0) I-III F508del/S1251N 3 (2.9) IV-V F508del/R75Q 1 (1.0) IV-V F508del/G542X 2 (1.9) I-III F508del/1717-1G N A 1 (1.0) I-III F508del/Ser489X 1 (1.0) I-III F508del/4382delA 1 (1.0) -a F508del/L1077 1 (1.0) I-III F508del/1813insC 1 (1.0) -b A455E/S1251N 1 (1.0) IV-V A455E/E60X 1 (1.0) IV-V 3272-26A N G/G970R 1 (1.0) IV-V 3272-26A N G/R1162X 1 (1.0) IV-V F508del/UNK 2 (1.9) -c R117H-7T/UNK 1 (1.0) -d UNK/UNK 1 (1.0) -e Total 104 (100.4) One patient with pancreatic sufficiency and diagnosed at 46 years of age (class IV-V). Login to comment

PMID: 24238947 [PubMed] Nshimyumukiza L et al: "Cost effectiveness of newborn screening for cystic fibrosis: a simulation study."

No. Sentence Comment

162 For example, the A455E mutation is more common (around 3%) in Quebec [48] and has been reported as a false negative for PAP results. Login to comment

PMID: 24357848 [PubMed] Zvereff VV et al: "Cystic fibrosis carrier screening in a North American population."

No. Sentence Comment

63 This threshold could not be reached Table 1ߒ CFTR allele frequency identified by the CF32 mutation panel Varianta Number of detected alleles Mutation (%) Legacy nomenclature HGVS nomenclature F508delb p.F508del 31,142 68.69 R117Hb p.R117H 5,198 11.46 G542Xb p.G542X 1,162 2.56 G551Db p.G551D 989 2.18 W1282Xb p.W1282X 824 1.82 3120ߙ+ߙ1G>Ab c.2988ߙ+ߙ1G>A 706 1.56 N1303Kb p.N1303K 648 1.43 R553Xb p.R553X 487 1.07 3849ߙ+ߙ10kbC>Tb c.3717ߙ+ߙ12191C>T 436 0.96 621ߙ+ߙ1G>Tb c.489ߙ+ߙ1G>T 410 0.90 1717-1G>Ab c.1585-1G>A 388 0.86 2789ߙ+ߙ5G>Ab c.2657ߙ+ߙ5G>A 382 0.84 I507delb p.I507del 258 0.57 R334Wb p.R334W 257 0.57 R1162Xb p.R1162X 211 0.47 G85Eb p.G85E 199 0.44 1898ߙ+ߙ1G>Ab c.1766ߙ+ߙ1G>A 170 0.37 R347Hc p.R347H 160 0.35 3659delCb c.3528delC 155 0.34 3876delAc c.3744delA 153 0.34 R560Tb p.R560T 132 0.29 S549Nc p.S549N 125 0.28 3905insTc c.3773dupT 121 0.27 R347Pb p.R347P 117 0.26 2184delAb c.2052delA 107 0.24 A455Eb p.A455E 106 0.23 711ߙ+ߙ1G>Tb c.579ߙ+ߙ1G>T 65 0.14 394delTTc c.262_263delTT 56 0.12 V520Fc p.V520F 54 0.12 1078delTc c.948delT 52 0.11 2183AA>Ga,c c.2051_2052delAAinsG 37 0.08 S549Rc p.S549R 31 0.07 Total 45,338 100 a 2183AA>G variant was added to the panel in 2010. b Variants from ACMG/ACOG CF screening panel. c Classified as a CF-causing mutation by the CFTR2 Database. ACMG, American College of Medical Genetics and Genomics; ACOG, American College of Obstetricians and Gynecologists; CF, cystic fibrosis; HGVS, Human Genome Variation Society. Table 2ߒ Continued on next page Table 2ߒ CFTR allele frequency identified by the CF69 mutation panel Varianta Allele frequency Mutation (%) Legacy nomenclature HGVS nomenclature F508delb p.F508del 1,868 60.49 R117Hb p.R117H 274 8.87 D1152Hc p.D1152H 125 4.05 G542Xb p.G542X 98 3.17 L206Wd p.L206W 73 2.36 3120ߙ+ߙ1G>Ab c.2988ߙ+ߙ1G>A 65 2.10 G551Db p.G551D 47 1.52 N1303Kb p.N1303K 42 1.36 W1282Xb p.W1282X 38 1.23 3849ߙ+ߙ10kbC>Tb c.3717ߙ+ߙ12191C>T 28 0.91 3876delAd c.3744delA 28 0.91 F311dele p.F312del 24 0.78 I507delb p.I507del 24 0.78 R553Xb p.R553X 24 0.78 R117Cd p.R117C 22 0.71 621ߙ+ߙ1G>Tb c.489ߙ+ߙ1G>T 21 0.68 1717-1G>Ab c.1585-1G>A 18 0.58 S549Nd p.S549N 18 0.58 R334Wb p.R334W 17 0.55 2789ߙ+ߙ5G>Ab c.2657ߙ+ߙ5G>A 16 0.52 G85Eb p.G85E 14 0.45 3199del6e c.3067_3072delATAGTG 12 0.39 R1066Cd p.R1066C 11 0.36 1898ߙ+ߙ1G>Ab c.1766ߙ+ߙ1G>A 10 0.32 R347Hd p.R347H 10 0.32 R1162 Xb p.R1162X 9 0.29 W1089Xd p.W1089X 9 0.29 2184delAb c.2052delA 8 0.26 2307insAd c.2175dupA 8 0.26 1078delTd c.948delT 7 0.23 R75Xd p.R75X 7 0.23 3120G>Ad c.2988 G>A 6 0.19 3659delCb c.3528delC 6 0.19 Q493Xd p.Q493X 6 0.19 R1158Xd p.R1158X 6 0.19 R560Tb p.R560T 6 0.19 1812-1G>Ad c.1680-1G>A 5 0.16 2055del9>Ad c.1923_1931del9insA 5 0.16 406-1G>Ad c.274-1G>A 5 0.16 A559Td p.A559T 5 0.16 R347Pb p.R347P 5 0.16 S1255Xd p.S1255X 5 0.16 1677delTAd c.1545_1546delTA 4 0.13 711ߙ+ߙ1G>Tb c.579ߙ+ߙ1G>T 4 0.13 E60Xd p.E60X 4 0.13 R352Qd p.R352Q 4 0.13 Y1092Xd p.Y1092X 4 0.13 2183AA>Gd c.2051_2052delAAinsG 3 0.10 3791delCd c.3659delC 3 0.10 3905insTd c.3773dupT 3 0.10 by 10 variants: the 2143delT, A455E, S549R, Y122X, and M1101K mutations, typically observed in Caucasians; 935delA, 2869insG, and Q890X in Hispanics; and 405+3A>C and G480C in the African-American population. Login to comment
66 The low frequency of the A455E mutation (0.07%) from the ACMG/ACOG panel may be explained by patient preselection through the use of the 32-mutation panel, or random drift. Login to comment
80 The Table 3ߒ Frequency of 5T/7T/9T genotypes as a result of R117H reflex testing Poly-T alleles Number of detected alleles (%) CF32 panel CF69 panel 5T/5T 23 (0.44) 2 (0.73) 5T/7T 430 (8.27) 26 (9.49) 5T/9T 38 (0.73) 1 (0.37) 7T/7T 4,103 (78.93) 219 (79.92) 7T/9T 604 (11.61) 26 (9.49) 9T/9T 1 (0.02) 0 Total 5,198 (100) 274 (100) 394delTTd c.262_263delTT 3 0.10 G178Rd p.G178R 3 0.10 V520Fd p.V520F 3 0.10 2143delTd c.2012delT 2 0.06 935delAe c.803delA 2 0.06 A455Eb p.A455E 2 0.06 Q890Xd p.Q890X 2 0.06 S549Rd p.S549R 2 0.06 2869insGd c.2737insG 1 0.03 405ߙ+ߙ3A>Ce c.273ߙ+ߙ3A>C 1 0.03 G480Ce p.G480C 1 0.03 M1101Kd p.M1101K 1 0.03 Y122Xd p.Y122X 1 0.03 Total 3,088 100 a 1898ߙ+ߙ5G>Te , 444delA, G330X, S364Pe , K710X, and S1196X mutations were not detected in the target population. Login to comment

PMID: 24416359 [PubMed] Cebotaru L et al: "Correcting the cystic fibrosis disease mutant, A455E CFTR."

No. Sentence Comment

0 Correcting the Cystic Fibrosis Disease Mutant, A455E CFTR Liudmila Cebotaru1,2 , Daniele Rapino1,2 , Valeriu Cebotaru3 , William B. Guggino2 * 1 Department of Ophthalmology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America, 3 Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America Abstract Cystic fibrosis is caused by more than 1000 mutations, the most common being the DF508 mutation. Login to comment
2 Here we have studied the class V mutation A455E. Login to comment
3 We report that the mature and immature bands of A455E are rapidly degraded primarily by proteasomes; the short protein half-life of this mutant therefore resembles that of DF508 CFTR. Login to comment
4 A455E could be rescued by treatment of the cells with proteasome inhibitors. Login to comment
5 Furthermore, co-transfection of A455E with the truncation mutant D264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. Login to comment
6 We found that D264 CFTR bound to A455E, forming a bimolecular complex. Login to comment
7 Treatment with the compound correctors C3 and C4 also rescued A455E. Login to comment
8 These results are significant because they show that although DF508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations. Login to comment
9 Citation: Cebotaru L, Rapino D, Cebotaru V, Guggino WB (2014) Correcting the Cystic Fibrosis Disease Mutant, A455E CFTR. Login to comment
26 One of these class V mutations is A455E. Login to comment
27 The A455E mutation is located in NBD1. Login to comment
30 Thus, because the mild disease resulting from A455E is thought to arise from reduced protein expression, it is considered a class V mutation. Login to comment
31 Thus, an effective pharmacological approach to treating this mutation should involve increasing the protein levels of A455E. Login to comment
35 The purpose of the current study was to determine whether analogous transcomplementation can be used to enhance the protein processing of A455E. Login to comment
37 Plasmids and constructs The construct pEGFP A455E was a gift from Dr. Gary Cutting at Johns Hopkins U. Login to comment
49 A455E has reduced expression of mature CFTR. Login to comment
50 Cos7 cells were transfected with 2 mg of wild-type, A455E, or DF508 CFTR constructs. Login to comment
52 Note that there is much less mature C band in the A455E sample than in the wild-type sample. Login to comment
53 In this and subsequent blots, some mature C band was detected with A455E (n = 8). Login to comment
56 Cells transfected with A455E cDNA were treated either with MG132, a more general inhibitor (n = 6) (A, B), or the more specific inhibitor of proteasomes, PS341 (n = 2) (C). Login to comment
57 Note that in both cases, proteasome inhibition caused an increase in both the immature B and mature C bands of A455E. Login to comment
58 doi:10.1371/journal.pone.0085183.g002 Results Expression of A455E When we compared the expression of the A455E mutant to that of both wild-type and nF508 CFTR (Fig. 1) by western blotting, we found that the amount of CFTR protein was greatly reduced in the Cos7 cells transfected with the A455E mutant. Login to comment
59 To evaluate the degradation of A455E CFTR, we treated the cells with MG132, a non-specific inhibitor of proteasomal degradation. Login to comment
60 Fig. 2 shows that in the presence of MG132, the protein expression of both the B and C bands of A455E CFTR increased dramatically. Login to comment
62 PS341 also caused an increase in both the B and C bands of A455E. Login to comment
63 Furthermore, we noted that A455E could be rescued by growing the cells at a reduced temperature, as had previously been observed for DF508 [13]. Login to comment
64 In sharp contrast, there was no increase in the protein expression of A455E CFTR when the cells were treated with the aggresome inhibitor tubacin or the lysosomal inhibitor E64 (Fig. 3). Login to comment
65 These data suggest that A455E is degraded primarily in proteasomes. Login to comment
66 To evaluate how rapidly the A455E CFTR protein is degraded, we treated the transfected cells with cycloheximide for between 1 and 7 hours (Fig 4). Login to comment
67 Surprisingly, both the B and C bands of A455E CFTR rapidly disappeared in the cells treated with cycloheximide (Fig. 4), suggesting that it is rapidly degraded, as is DF508 CFTR (see [13]). Login to comment
68 n264 CFTR increases the processing of band B to band C of A455E CFTR We then tested whether the truncation mutant, n264 CFTR, was capable of transcomplementation with A455E (Fig. 5). Login to comment
69 In order to determine whether D264 CFTR affects the maturation of A455E CFTR, we cotransfected D264 CFTR and A455E CFTR into Cos7 cells and found that the mature C band from A455E CFTR was increased in cells cotransfected with D264 CFTR, as compared to cells transfected with A455E cDNA alone (Fig. 5). Login to comment
72 Cos7 cells were transfected with A455E CFTR cDNA and treated for 16 h with the lysosome inhibitor E64 (n = 4) (A) There was very little change in band density in any of the treated groups or in the presence of the inhibitors when compared to the control or the HDAC6 inhibitor tubacin to inhibit aggresomes (n = 3) (B, C). Login to comment
74 doi:10.1371/journal.pone.0085183.g003 n264 CFTR binds to A455E CFTR, forming a biomolecular complex We and others have shown that transcomplementation can occur via direct binding of truncated forms of CFTR to DF508-CFTR and via chaperone displacement [17]. Login to comment
75 In order to assess these possibilities in A455E CFTR, we conducted co-immunpre- cipitation experiments. Login to comment
76 Fig. 6 shows that D264-CFTR did indeed bind to A455E, in both the absence and presence of the proteasome inhibitor MG123. Login to comment
77 Correctors 4A (C4) and VX325 (C3) increase the processing of band B to band C of A455E CFTR We next asked whether small-molecule correctors might be effective in rescuing A455E CFTR (Fig. 7). Login to comment
79 We found that corrector C4 does have a robust effect on A455E CFTR; in contrast, C3 had only a minimal effect on A455E (Fig. 7). Login to comment
83 Here we show that A455E can also be rescued by transcomplementation. Login to comment
87 The A455E mutation, on the other hand, is located within the F1-type ATP-binding core subdomain near to the ABC protein signature, the Walker A domain [24]. Login to comment
88 Given the proximity to the Walker A domain, one might expect that A455E would have alterations in gating. Login to comment
90 A455E also functions well as a regulator of other channels [25]. Login to comment
93 At least two studies have failed to detect mature band C from A455E [11,26], although the results of their electrophysiological studies suggested that some mature band C must have been present at the plasma membrane in order to generate chloride currents [11]. Login to comment
94 In our study, we do detect some mature band C at the plasma membrane, but when the cells are treated with cycloheximide to evaluate protein degradation, it is clear that the mature band C of A455E is rapidly degraded along with the immature B band. Login to comment
98 have shown that A455E has a pattern of degradation that is clearly different from that of DF508 CFTR. Login to comment
99 A455E appears to be proteolytically cleaved within the NBD1-R domain to form C-terminal aggregates. Login to comment
101 Clearly, these results show that the A455E mutant is distinctly different from DF508 CFTR. Login to comment
102 Nevertheless, A455E shows some similarity to DF508 CFTR. Login to comment
103 Although A455E is uniquely cleaved in the cytoplasm, our results show that it is still degraded in the proteasome, because treatment with two types of proteasome inhibitors led to significant increases in steady-state protein levels. Login to comment
104 In fact, we saw a rather large increase in the mature band of A455E after proteasome inhibition. Login to comment
105 This result is in contrast to the response of A455E to lysosomal inhibitors, which were without effect. Login to comment
107 A455E binds to n27-264 CFTR. Login to comment
108 Cos7 cells were transfected with both D27-264 CFTR and an A455E CFTR construct bearing a GFP tag. Login to comment
109 Anti-GFP antibodies were used to pull down A455E, and the gels were blotted with anti-CFTR antibody. Login to comment
113 Transcomplementation of A455E by D27-264 CFTR. Login to comment
114 Both the C and B bands of A455E CFTR were increased when cells were cotransfected with D27-264 CFTR, showing that A455E could be rescued by transcomplementation. Login to comment
117 Effect of protein synthesis inhibition on the degradation of A455E. Login to comment
118 Cos7 cells were transfected with A455E cDNA and treated with cycloheximide (25 mg/ml) for the indicated times. Login to comment
119 Note the rapid decay of both the mature C and immature B bands of A455E. Login to comment
122 Taken together, our data suggest that A455E, like DF508 CFTR, is processed by proteasomes. Login to comment
123 D264 CFTR rescues A455E and forms a molecular complex between the two molecules. Login to comment
126 It is possible that a similar interaction occurs between D264 and A455E. Login to comment
131 The observation that A455E is readily rescued by D264 CFTR suggests that transcomplementation may be influencing NBD1 in the region of the Walker sites. Login to comment
132 One then may ask why the interaction with the normal NBD2 of A455E does not rescue its own NBD1. Login to comment
138 Correctors can rescue A455E. Login to comment
139 Cos7 cells were transfected with A455E and treated with the correctors C3 or C4 for 16 h at the specified concentrations. Login to comment
140 Note that C4 had a profound effect on the immature B band of A455E as well as causing an increase in the mature C band (A, B). Login to comment
143 doi:10.1371/journal.pone.0085183.g007 Therapeutic transcomplementation to rescue A455E would require gene transfer via a virus or non-viral particle. Login to comment
150 Our demonstration that both C3 and C4 can rescue A455E suggests that A455E CFTR may be a better candidate for correction with either compound correctors or transcomplementation than is DF508 CFTR. Login to comment

PMID: 24440181 [PubMed] De Boeck K et al: "The relative frequency of CFTR mutation classes in European patients with cystic fibrosis."

No. Sentence Comment

30 Finally, class V mutations result in a markedly decreased amount of CFTR protein with normal function at the epithelial cell membrane and include splice site mutations that only partially disturb correct splicing (e.g. 3849+10KbCNT and 2789+5GNA) or mutant CFTR that only partially matures (e.g. A455E). Login to comment
56 Class Type of defect List of mutations attributed to this class Class I Defective protein production Nonsense mutations Large deletions and insertions 1078delT; 1717-1G࢐A; 3659delC; 621+1G࢐T Class II Defective protein processing G85E, F508del, I507del, R560T, N1303K Class III Defective protein regulation ('gating`) G178R, S549N, S549R, G551D, G551S, G970R, G1244E, S1251N, S1255P, G1349D Class IV Defective protein conductance R117H, R334W, R347P Class V Reduced amount of functioning protein 2789+5G࢐A, 3849+10KbC࢐T, A455E Unclassified All other mutations, including those unknown. Login to comment

PMID: 24513262 [PubMed] Sarles J et al: "Neonatal screening for cystic fibrosis: comparing the performances of IRT/DNA and IRT/PAP."

No. Sentence Comment

158 IRT d3 Ctrl IRT PAP Cl- Mut 1 Mut 2 1 66 68 0.4 80 ƊF508del ƊF508del 2 87.8 106.5 0.5 137 E1104X E1104X 3 93.2 105.8 0.8 82 G91R ƊF508del 4 71.1 56.7 0.3 80.0 ƊF508del ƊF508del 5 67.9 54.4 1.5 99.0 ƊF508del ƊF508del 6 87.1 82.9 4.5 70.0 E1104X D110H 7 61.5 62 5.0 88.0 R553X A455E 8 62.4 63.0 14.6 110.0 2183AANG 907delCins11 9 117.0 81.5 15.6 130.0 S466X S466X Lines 1-3: false negatives in the IRT/PAP strategy, 6-9: false negatives in the IRT/DNA strategy, due to mutations not detected by the Elucigeneࡊ CF30, 45: false negatives in both strategies. Login to comment

PMID: 24517344 [PubMed] Raju SV et al: "Impact of heterozygote CFTR mutations in COPD patients with chronic bronchitis."

No. Sentence Comment

81 As expected based on genotype-phenotype correlations in the disease [33], HBE cells derived from a F508del CFTR heterozygote had slightly lower CFTR activity at baseline than wild type monolayers as measured by Table 1 List of CFTR mutations analyzed F508del R117H 1717-1G > A R117C G85E R334W 1898 + 1G > A Y122X A455E R347P 2184delA G178R I507del R553X 2789 + 5G > A G314E G542X R560T 3120 + 1G > A G330X G551D W1282X 3659delC R347H N1303K 621 + 1G > T K710X 406-1G > A R1162X 711 + 1G > T E60X G480C R1066C W1089X V520F A559T S1196X Q1238X S1251N S1255X 663delT 935delA 1161delC 1288insTA 2184insA 2307insA 2711delT 2869insG R709X R764X R1158X 574delA Q493X 1898 + 5G > T 3905insT I506T 3849 + 10kbC > T 712-1G > T Q98R Q552X S549N 1078delT H199Y 444delA S549R (T > G) 2143delT P205S 2043delG 1811 + 1.6kbA > G 3272-26A > G L206W 3791delC Y1092X (C > G) 3199del6 F508C 2108delA Y1092X (C > A) D1152H V520I 3667del4 394delTT 3876delA M1101K 1677delTA W1098X (TGA) 1812-1G > A 4016insT 1609delCA 3171delC response to forskolin stimulation (49.3 &#b1; 11.5 bc;A/cm2 in CFTR (+/+) vs. 40.5 &#b1; 5.3 bc;A/cm2 in CFTR (+/-), although this was not statistically significant (Figure 1A,B). Login to comment

PMID: 24532752 [PubMed] Lane MA et al: "A new era in the treatment of cystic fibrosis."

No. Sentence Comment

12 > Class V defects (eg A455E) result in overall reduced synthesis of normal CFTR. Login to comment

PMID: 24561283 [PubMed] Ikpa PT et al: "Cystic fibrosis: toward personalized therapies."

No. Sentence Comment

1687 Normalized non-corrected FIS rates differed greatly between different CFTR genotypes (non-CF > class V (A455E) > class II (F508del) > class I), and, perhaps less evident, between individuals carrying the same alleles (i.e. F508del/F508del). Login to comment

PMID: 24586523 [PubMed] Zietkiewicz E et al: "CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients."

No. Sentence Comment

71 Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans Pathogenic mutations 1 1 L15Ffs10X c.43delC 175delC 1 CFMDB 1717-1G.A 2 2 G27V 21.92 c.80G.T 212G.T 1 Novel F508del 2 2 S18RfsX16 c.54-5940_273 +10250del21kb exon2,3del21kb 66 IL19 various CF mutations i2 i2 IVS2_Donor c.164+1G.A 296+1G.A 3 CFMDB various CF mutations 3 3 G85E 22.61 c.254G.A 386G.A 1 IL17 unknown 3 3 E60X c.178G.T 310G.T 0 IL17 x 3 3 L88IfsX22 c.262_263delTT 394delTT 0 IL17 x 4 4 E92K 21.92 c.274G.A 406G.A 2 CFMDB c.164+1G.A; c.2051- 2AA.G 4 4 L101X c.302T.G 434T.G 1 CFMDB c.3717+12191C.T 4 4 K114IfsX5 c.341_353del13bp 473del13bp 1 Novel F508del 4 4 R117H 20.35 c.350G.A 482G.A 5 IL17 F508del; 2x unknown 4 4 R117C 22.07 c.349C.T 481C.T 2 CFMDB S1206X;1x unknown 4 4 L137_L138insT c.412_413insACT L138ins 1 CFMDB F508del 4 4 R153I 22.61 c.458G.T 590G.T 2 Novel F508del; c.3527delC i4 i4 IVS4_Donor c.489+1G.T 621+1G.T 5 IL17 F508del; c.489+1G.T 5 5 L165X c.494T.A 626T.A 1 Novel F508del i5 i5 IVS5_Donor c.579+1G.T 711+1G.T 0 IL19 x i5 i5 IVS5_Donor c.579+3A.G 711+3A.G 2 CFMDB 2,3del21kb; c.2052-3insA i5 i5 IVS5_Donor c.579+5G.A 711+5G.A 0 IL17 x 7 8 F311L 20.90 c.933C.G 965C.G 2 CFMDB 2x F508 7 8 G314R 20.58 c.940G.A 1072G.A 4 CFMDB various CF mutations 7 8 F316LfsX12 c.948delT 1078delT 1 IL17 unkown 7 8 R334W 22.41 c.1000C.T 1132C.T 6 IL17 various CF mutations 7 8 I336K 22.07 c.1007T.A 1139T.A 2 CFMDB 2,3de21kb; F508del 7 8 R347P 22.27 c.1040G.C 1172G.C 11 IL17 various CF mutations i7 i8 IVS8_Donor c.1116+2T.A 1248+2T.A 1 Novel Q1412X 9 10 A455E 22.61 c.1364C.A 1496C.A 0 IL17 x i9 i10 IVS10_Donor c.1392+1G.A 1524+1G.A 1 CFMDB c.3816-7delGT 10 11 S466X c.1397C.G 1529C.G 1 CFMDB G542X 10 11 I507del c.1519_1521delATC 1651delATC 2 IL19 F508del 10 11 F508del c.1521_1523delCTT 1654delCTT 805 IL19 various CF mutations i10 i11 IVS11_Acceptor c.1585-1G.A 1717-1G.A 27 IL19 various CF mutations 11 12 G542X c.1624G.T 1756G.T 25 IL19 various CF mutations 11 12 G551D 21.24 c.1624G.T 1756G.T 5 IL19 various CF mutations 11 12 Q552X c.1654C.T 1786C.T 0 IL19 x 11 12 R553X c.1657C.T 1789C.T 14 IL19 various CF mutations 11 12 R560T 21.92 c.1679G.C 1811G.C 0 IL19 x i12 i13 IVS13_Donor c.1766+1G.A 1898+1G.A 6 IL19 various CF mutations i12 i13 IVS13_Donor c.1766+1G.C 1898+1G.C 1 CFMDB F508del 13 14 H620P 21.73 c.1859A.C 1991A.C 1 CFMDB F508del 13 14 R668C//G576A 21.61//1.73 c.2002C.T//c.1727G.C 2134C.T// 1859G.C 5 b CFMDB// rs1800098 c.1585-1G.A; 4 unknown 13 14 L671X c.2012delT 2143delT 27 IL17 various CF mutations 13 14 K684SfsX38 c.2051_2052delAAinsG 2183AA.G 10 IL17 various CF mutations 13 14 K684NfsX38 c.2052delA 2184delA 0 IL17 x 13 14 Q685TfsX4 c.2052_2053insA 2184insA 15 CFMDB various CF mutationsc , 1 unknown Table 2. Cont. Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans 13 14 L732X c.2195T.G 2327T.G 1 CFMDB F508del 14A 15 R851X c.2551C.T 2683C.T 3 CFMDB various CF mutations 14A 15 I864SfsX28 c.2589_2599del11bp 2721del11bp 2 CFMDB F508del; 2,3del21kb i14B i16 IVS16_Donor c.2657+2_2657+3insA 2789+2insA 1 CFMDB F508del i14B i16 IVS16_Donor c.2657+5G.A 2789+5G.A 0 IL17 unkown 15 17 Y919C 21.02 c.2756A.G 2888A.G 1 CFMDB unknown 15 17 H939HfsX27 c.2817_2820delTACTC 2949delTACTC 1 Novel unkown i15 i17 IVS17_Donor c.2908+3A.C 3040+3A.C 1 Novel F508del i16 i18 IVS18_Donor c.2988+1G.A 3120+1G.A 0 IL19 x 17A 19 I1023_V1024del c.3067_3072delATAGTG 3199del6 0 IL19 x i17A i19 IVS19 c.3140-26A.G 3272-26A.G 9 IL19 various CF mutations 17B 20 L1065R 21.90 c.3194T.G 3326T.G 1 CFMDB F508del 17B 20 Y1092X c.3276C.A 3408C.A 1 CFMDB R334W i18 i21 IVS21_Donor c.3468+2_3468+3insT 3600+2insT 11 CFMDB various CF mutationsd , 1 unknown 18 21 E1126EfsX7 c.3376_3379delGAAG 3508delGAAG 1 Novel F508del 19 22 R1158X c.3472C.T 3604C.T 2 CFMDB F508del; R553X 19 22 R1162X c.3484C.T 3616C.T 1 IL17 F508del 19 22 L1177SfsX15 c.3528delC 3659delC 4 IL17 various CF mutations 19 22 S1206X c.3617C.A 3749C.A 1 CFMDB R117C i19 i22 IVS22 c.3717+12191C.T 3849+10kbC.T 58 IL17 various CF mutations 20 23 G1244R 22.62 c.3730G.C 3862G.C 1 CFMDB F508del 20 23 S1251N 22.28 c.3752G.A 3884G.A 0 IL19 x 20 23 L1258FfsX7 c.3773_3774insT 3905insT 0 IL19 x 20 23 V1272VfsX28 c.3816_3817delGT 3944delGT 1 CFMDB c.1392+1G.A 20 23 W1282X c.3846G.A 3978G.A 9 IL19 various CF mutations 21 24 N1303K 22.62 c.3909C.G 4041C.G 18 IL19 various CF mutations 22 25 V1327X c.3979delG 4111delG 1 Novel F508del 22 25 S1347PfsX13 c.4035_4038dupCCTA c.4167dupCCTA 1 CFMDB 2,3del21kb 23 26 Q1382X c.4144C.T 4276C.T 1 CFMDB F508del 23 26 Q1412X c.4234C.T 4366C.T 2 CFMDB F508del; c.1116+2T.A i23 i26 IVS26_Donor c.4242+1G.T 4374+1G.T 1 CFMDB F508del Sequence changes of uncertain pathogenic effect, tentatively counted as mutations 6A 6 E217G 0.30 c.650A.G 782A.G 1 CFMDB; rs1219109046 unknown 7 8 R352Q 20.01 c.1055G.A 1187G.A 1 CFMDB; rs121908753 F508del 7 8 Q359R 0.33 c.1076A.G 1208A.G 1 CFMDB F508del i8 i9 IVS9 c.1210-12T5_1210- 34_35 (TG)12 1332-12Tn_- 34TGm 6 CFMDB F508del; 3x unknown i8 i9 IVS9 c.1210-12T5_1210- 34_35 (TG)13 1332-12Tn_- 34TGm 2 CFMDB 2143delT; 1x unknown i8 i9 IVS9 c.1210-12T8 1332-12Tn 1 Novel unknown 10 11 I506V 20.21 c.1516A.G 1648A.G 1 CFMDB; rs1800091 unknown 12 13 V562L 0.79 c.1684G.C 1816G.C 1 CFMDB; rs1800097 unknown 13 14 G723V 0.44 c.2168G.T 2300G.T 1 CFMDB; rs200531709 unknown 15 17 D924N 0.03 c.2770G.A 2902G.A 1 CFMDB; rs201759207 unknown patient with F508del on another allele) was not supported by the SVM value (+0.35); the patient was PS and had ambiguous chloride values (45, 64 and 83 mmol/L). 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103 IL17 (INNOLiPA_CFTR17_TnUpdate): 621+1G.T; 3849+10kbC.T; 2183AA.G; 394delTT; 2789+5G.A; R1162X; 3659delC; R117H; R334W; R347P; G85E; 1078delT; A455E; 2143delT; E60X; 2184delA; 711+5G.A; polymorphism 5T/7T/9T. Login to comment

PMID: 24631642 [PubMed] Fanen P et al: "Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies."

No. Sentence Comment

74 23 ACMG recommended panel of classic CF-causing mutations G85E R117H R334W R347P A455E I507del F508del G542X G551D R553X R560T R1162X W1282X N1303K 621 + 1G > T 711 + 1G > T 1717 - 1G > A 1898 + 1G > A 2184delA 2789 + 5G > A 3120 + 1G > A 3659delC 3849 + 10kbC > T Additional or alternative mutations present at significant frequencies in an ethnic population served by a newborn screening program may be assessed. Login to comment

PMID: 24727426 [PubMed] Wang Y et al: "Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models."

No. Sentence Comment

2026 This class of CF mutations includes promoter mutations that alter transcription (e.g. 125 G࢐C), nucleotide changes that promote alterative splicing of CFTR transcripts (e.g. 3849 + 10 kb C࢐T) and amino acid substitutions, which cause inefficient protein maturation (e.g. A455E) (Zielenski and Tsui, 1995). Login to comment
2028 This idea is exemplified by A455E, the first CF-PS mutation to be associated with milder lung disease (Gan et al., 1995). Login to comment
2029 When studied in heterologous cells, A455E-CFTR disrupted the processing and intracellular transport of CFTR, albeit not as severely as F508del-CFTR (Sheppard et al., 1995). Login to comment
2030 However, the conduction, permeation and gating properties of A455E-CFTR were almost indistinguishable from those of wild-type CFTR (Sheppard et al., 1995). Login to comment

PMID: 24932877 [PubMed] Bell SC et al: "New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls."

No. Sentence Comment

544 Mutation Alternative name Allele frequency (% of total known) in ECFSPR 2010 Allele frequency (% of total known mutations) in 2010 ECFSPR F508del 64.5 Most frequent mutation worldwide Southeast to Northwest increasing prevalence in Europe IL 25.5 to DK 82.6 Mutations with an overall EU prevalence above 1% G542X Mediterranean mutation 2.5 GR 6.7, ES 6.0 N1303K Ancient Phoenician mutation 1.9 IT 4.2 W1282X Jewish Ashkenazi mutation 1.2 IL 22.4 G551D Celtic mutation 1.1 IE 7.3 1717-1GNA Italian mutation 1.0 IT 3.7 Mutations with an overall EU prevalence below 0.5% G85E PT 3.5 A455E Dutch mutation NL 3.5 CFTR dele 2,3 Slavic mutation CZ 5.2, BY 6.7 394delTT Nordic mutation SE 7.9, DK 2.0 3905insT Swiss mutation CH 2.4 R1162X Italian mutation IT 7.8 A561E Portuguese mutation PT 3.2 Abbreviations ECFSPR - European Cystic Fibrosis Society Patient Registry. Login to comment
547 Class Type of defect List of mutations attributed to this class Class I Defective protein production Nonsense mutations: G542X, R1162X, RW1282X Deletions and insertions: CFTRdele2,3; 1078delT; 1717-1G ࢐ A; 3659delC; 621+1G N T Class II Defective protein processing G85E, F508del, I507del, R560T, A561E, R1066C, N1303K Class III Defective protein regulation (gating) G178R, S549N, S549R, G551D, G551S, G970R, G1244E, S1251N, S1255P, G1349D Class IV Defective protein conductance R334W, R347P, R117H Class V Reduced amount of functioning protein 2789+5G ࢐ A, 3272-26ANG, 3849+10KbC ࢐ T, A455E Class VI Reduced cell surface stability Rescued F508del, c.120del23 Unclassified All other mutations, including those unknown a F508del-CFTR pocket (at NBD1:ICL4 interface) (Farinha et al., 2013). Login to comment

PMID: 25003014 [PubMed] Dekkers JF et al: "Novel opportunities for CFTR-targeting drug development using organoids."

No. Sentence Comment

41 FIS varied greatly between organoids derived from different CF subjects, and was largest in organoids from patients with milder CF that express CFTR-A455E.17,24 We detected FIS in all organoids expressing CFTR-F508del, also when it was expressed from just a single allele. Login to comment

PMID: 25033378 [PubMed] LaRusch J et al: "Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis."

No. Sentence Comment

269 67 SNPs (125GtoC, 1716G.A, 1717-1G.A, 1898+1G.A, 2183AA.G, 2184delA, 2789+5G.A, 3120+1G.A, 3659delC, 3849+10kbC.T, 621+ 1G.T, 711+5G.A, A455E, D110H, D1152H, D1270N, D443Y, D579G, F1052V, F1074L, F508C, F508del, G1069R, G1244E, G1349D, G178R, G542X, G551D, G551S, I1131L/V, I148T, I336K/T, I507del, I807M, IVS8T5, K1180T, L1065P, L967S, L997F, M1V, M470V, M952I, M952T, N1303K, P67L, Q1463Q, R1070Q, R1162X, R117C, R117H, R170H, R258G, R297Q, R31C, R352Q, R553X, R668C, R74W, R75Q, S1235R, S1255P, S485R, S977F, T338I, T854T, V201M, W1282X) were multiplexed into 6 wells; 14 SNPs (S492F, S945L, R74Q, R560T, R1162L, G85E, I1027T, R334W, R347P, G576A, 711+1G.T, 1001+11C.T, P1290P, 3199del6) were ascertained separately via TaqMan Gene Expression Assays, with repeat confirmation of all positive results. Login to comment

PMID: 25077647 [PubMed] Lyon E et al: "Molecular genetic testing for cystic fibrosis: laboratory performance on the College of American Pathologists external proficiency surveys."

No. Sentence Comment

106 The lowest analytical sensitivity (91.1%) for a single challenge was recorded for a 2003 compound heterozygous sample (621+1G>T/A455E). Login to comment
118 90 95 A (621 + 1G>T/A455E) (G542X/G542X) (I507 wild type or negative?) Login to comment

PMID: 25122143 [PubMed] Audrezet MP et al: "Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy."

No. Sentence Comment

53 Because only a limited number of functional studies have assessed the pathogenicity of variants, mutations have been classified in previous studies according to their disease-causing potential.16,22,23 Based on the recommendations and data from these studies (UMD-CFTR-France),24 variants were classified into four groups: A, CF-causing; B, associated with CFTR-RDs; C, no clinical consequences; and D, unknown or Table 1ߒ Allelic frequencies of CF30-kit mutations, identified in neonates with CF, and correspondence between traditional mutation nomenclature and that on the Human Genome Variation Society website Frequency (F) % Mutation Legacy mutation nomenclature Number of alleles/2,320 % of alleles/2,320 Cumulative % ࣙ5 p.Phe508del F508del 1,560 67.24 67.24 p.Gly542* G542X 113 3.19 10.51 p.Asn1303Lys N1303K 81 1.98 c.1585-1G>A 1717-1G>A 48 1.47 1.00ࣙFࣙ4.99 c.2657ߙ+ߙ5G>A 2789ߙ+ߙ5G>A 37 1.42 p.Arg553* R553X 36 1.29 p.Gly551Asp G551D 31 1.16 p.Tyr122* Y122X 26 0.97 6.86 c.2988ߙ+ߙ1G>A 3120ߙ+ߙ1G>A 22 0.82 c.579ߙ+ߙ1G>T 711ߙ+ߙ1G>T 18 0.67 p.Ile507del I507del 17 0.63 c.3140-26A>G 3272-26A>G 16 0.59 0.40ࣙFࣙ0.99 p.Arg347Pro R347P 15 0.56 p.Arg1162* R1162X 15 0.56 p.Trp1282* W1282X 14 0.52 p.Tyr1092* Y1092X 13 0.48 c.2051_2052delinsG 2183AA>G 12 0.45 c.3528delC 3659delC 11 0.41 c.1680-886A>G 1811ߙ+ߙ1.6kbA>G 9 0.39 p.Gly85Glu G85E 8 0.34 3.06 p.Ser1251Asn S1251N 7 0.30 p.Arg334Trp R334W 7 0.30 p.Arg117His R117H 7 0.30 0.1ࣙFࣙ0.39 p.Trp846* W846X 6 0.26 c.489ߙ+ߙ1G>T 621ߙ+ߙ1G>T 6 0.26 c.948delT 1078delT 5 0.22 p.Ala455Glu A455E 5 0.22 p.Glu60* E60X 4 0.17 c.262_263delTT 394delTT 4 0.17 c.3718-2477C>T 3849ߙ+ߙ10kbC>T 3 0.13 Total 2,034 87.67 87.67 Mutations are clustered into four groups of frequency intervals (>5%, 1-4.99%, 0.99-0.4%, and <0.4%). Login to comment

PMID: 25287046 [PubMed] Mornon JP et al: "Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics."

No. Sentence Comment

360 The effects of remaining mutations listed in CFTR2 database can also be well understood in light of our structural data: (1) A455E has indeed no room to be well adapted, (2) G1244E (mentioned above) also occurs in a well conserved position (position 23 in Online Resource 2), (3) L467P might disturb the helix in which it is included, (4) G1349D is in the non-canonical ATP-binding site and, alike its corresponding G551D, has no room to be well adapted in presence of ATP, and finally (5) N1303K might disturb the large Q-loop of the NBD2 a-helical subdomain (position 42 in Online Resource 1 and Online Resource 2). Login to comment

PMID: 25799511 [PubMed] Rapino D et al: "Rescue of NBD2 mutants N1303K and S1235R of CFTR by small-molecule correctors and transcomplementation."

No. Sentence Comment

38 We have recently shown that another NBD1 mutant, A455E, can be rescued [12]. Login to comment
209 Transcomplementation by Ɗ27-264 is able to rescue NBD2 mutants We have previously shown that truncated forms of CFTR such as Ɗ264 and Ɗ27-264-CFTR can rescue the NBD1 mutants ƊF508-CFTR and A455E CFTR [27,42], but it was still not clear whether the NBD2 mutants could also be transcomplemented. Login to comment
244 Unlike ƊF508-CFTR and A455E, both of which undergo significant trafficking of immature band B to mature band C [12], the mature bands of N1303K and S1235R are not enhanced when cells are grown at low temperature. Login to comment
251 This response of S1235R is in sharp contrast to that of A455E, which is not sensitive to tubacin. Login to comment
259 These results point to differences in the processing of these NBD2 mutants when compared to two of the mutations in NBD1, A455E and ƊF508-CFTR. Login to comment
322 2012; 67: 12-18. doi: 10.1136/thoraxjnl-2011-200393 PMID: 21825083 12. Cebotaru L, Rapino D, Cebotaru V, Guggino WB Correcting the cystic fibrosis disease mutant, A455E CFTR. Login to comment

PMID: 25874479 [PubMed] Loukas YL et al: "Clinical diagnostic Next-Generation sequencing: the case of CFTR carrier screening."

No. Sentence Comment

36 Sample code Source Genotype NA18668*2 Coriell Cell Repositories* CFTR, CFdelex2,3/p.F508del NA07830 Coriell Cell Repositories* CFTR, F508del/556delA NA11275 Coriell Cell Repositories* CFTR, 3659delC/F508del NA11277 Coriell Cell Repositories* CFTR, I507del/wt NA11860 Coriell Cell Repositories* CFTR, 3849af9;10kb,Cb0e;T/3849af9;10kb,Cb0e;T 40C2 CDC** CFTR, F508del/R334W 10C4 CDC** CFTR, 2184delA/394delTT CDC2 CDC** CFTR, F508del/Exon 17&#aa;-17b-18del 212C4 CDC** CFTR, F508del/3659delC 412C2 CDC** CFTR, F508del/R334W 213C4 CDC** CFTR, W1282X/W1282X 21C2 CDC** CFTR, 1717-1Gb0e;A/1154insTC 412C5 CDC** CFTR, F508del/2183AAb0e;G 412C1 CDC** CFTR, 2184delA/394delTT 212C5 CDC** CFTR, F508del/3849af9;10KbCb0e;T 38C4 CDC** CFTR, R553X/wt 48C1 CDC** CFTR, F508del/G542X 48C3 CDC** CFTR, F508del/G551D 19C4 CDC** CFTR, F508del/R560T 19C5 CDC** CFTR, G551D/G551D 29C3 CDC** CFTR, 621af9;1Gb0e;T/N1303K 29C5 CDC** CFTR, F508del/2789af9;5Gb0e;A 49C1 CDC** CFTR, 3120af9;1Gb0e;A/L467P# 49C3 CDC** CFTR, 621af9;1Gb0e;T/R1162X 40C5 CDC** CFTR, 711af9;1Gb0e;T/wt 21C1 CDC** CFTR, A455E/F508del 112C2 CDC** CFTR, 1898af9;1Gb0e;A/F508del 214C5 CDC** CFTR, F508del/3140-26Ab0e;G *http://ccr.coriell.org/; **CDC, Center for Disease Control & Prevention, http://www.cdc.gov/; #According to CDC report, its clinical significance is unknown. Login to comment
94 Mutation cDNA Coverage Score Reference allele (F/R strand) Mutant allele (F/R strand) Genotype F508del* c.1521_1523delCTT 2080 26.5 491/557 523/504 HET 556delA c.424delA 2168 26.7 524/557 547/536 HET 3659delC* c.3528delC 2359 27.0 573/605 566/609 HET I507del c.1519_1521delATC 2246 26.8 508/612 619/501 HET 3849af9;10kb,Cb0e;T c.3717af9;12191Cb0e;T 3596 28.4 - 1834/1756 HOM 3849af9;10kb,Cb0e;T c.3717af9;12191Cb0e;T 4169 29.0 1023/1059 1116/967 HET R334W* c.1000Cb0e;T 2473 27.1 636/599 626/609 HET 2184delA* c.2052delA 3069 27.9 734/801 792/738 HET 394delTT* c.262_263delTT 3176 28.0 775/811 819/766 HET W1282X c.3846Gb0e;A 4268 29.0 - 2168/2096 HOM 1717-1Gb0e;A c.1585-1Gb0e;A 3863 28.7 922/1007 985/944 HET 1154insTC c.1022_1023insTC 4021 28.8 1058/1039 979/941 HET 2183AAb0e;G c.2051_2052delAAinsG 3927 28.8 1023/996 974/926 HET R553X c.1657Cb0e;T 6027 30.2 1532/1480 1476/1534 HET G542X c.1624Gb0e;T 3862 28.7 933/996 925/1002 HET G551D c.1652Gb0e;A 5225 29.7 1257/1351 1341/1268 HET G551D c.1652Gb0e;A 4862 29.5 - 2487/2369 HOM R560T c.1679Gb0e;C 3542 28.4 861/908 915/853 HET 621af9;1Gb0e;T* c.489af9;1Gb0e;T 2256 26.8 534/592 606/519 HET N1303K c.3909Cb0e;G 2126 26.6 534/528 492/568 HET 2789af9;5Gb0e;A c.2657af9;5Gb0e;A 3453 28.3 824/901 895/828 HET 3120af9;1Gb0e;A c.2988af9;1Gb0e;A 3021 27.8 721/787 802/707 HET L467P c.1400Cb0e;T 3848 28.7 928/993 1003/920 HET R1162X c.3484Cb0e;T 4180 29.0 1021/1065 1112/976 HET 711af9;1Gb0e;T c.579af9;1Gb0e;T 4222 29.0 1036/1072 1001/1108 HET A455E c.1364Cb0e;A 5621 30.0 1365/1443 1438/1370 HET 1898af9;1Gb0e;A c.1766af9;1Gb0e;A 2934 27.7 683/782 702/762 HET 3272-26Ab0e;G 3140-26Ab0e;G 3755 28.6 902/973 1008/867 HET of the majority of CFTR mutations carriers in our region. Login to comment

PMID: 25920899 [PubMed] Bilodeau C et al: "Deleterious impact of hyperglycemia on cystic fibrosis airway ion transport and epithelial repair."

No. Sentence Comment

46 Primary human airway nasal cells were recovered after polypectomy procedures from CF patients with various genotypes (four homozygous ƊF508/ƊF508, two ƊF508/N1303, one ƊF508/undefined and one ƊF508/A455E, median age 21.5 yrs, mean FEV1 of 83.1 &#b1; 6.1%), according to protocols approved by the CHUM ethical committee and with written informed consent by the patients. Login to comment

PMID: 25940043 [PubMed] Corvol H et al: "Translating the genetics of cystic fibrosis to personalized medicine."

No. Sentence Comment

65 A p.Ala455Glu (A455E) 0.3% c.1585-1G , A - (1717-1G , A) 0.89% c.2052delA p.Lys684AsnfsX38 (2184delA) 0.16% c.3484C . Login to comment

PMID: 26014425 [PubMed] Girardet A et al: "The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus."

No. Sentence Comment

78 Table 1 Examples of common CF-causing, indetermined, and non CF-causing variants (modified from5,8,17) HGVS nomenclature Legacy name cDNA nucleotide name Protein name CF-causing variantsa F508del c.1521_1523delCTT p.Phe508del G542X c.1624G4T p.Gly542* G551D c.1652G4A p.Gly551Asp N1303K c.3909C4G p.Asn1303Lys W1282X c.3846G4A p.Trp1282* 621+1G4T c.489+1G4T CFTRdele2,3 c.54-5940_273 +10250del21080 p.Ser18Argfs*16 E60X c.178G4T p.Glu60* G85E c.254G4A p.Gly85Glu 394delTT c.262_263delTT p.Leu88Ilefs*22 711+1G4T c.579+1G4T R347P c.1040G4C p.Arg347Pro A455E c.1364C4A p.Ala455Glu Q493X c.1477C4T p.Gln493* I507del c.1519_1521delATC p.Ile507del R553X c.1657C4T p.Arg553* R560T c.1679G4C p.Arg560Thr 1898+1G4A c.1766+1G4A 2183AA4G c.2051_2052delAAinsG p.Lys684Serfs*38 2789+5G4A c.2657+5G4A 3120+1G4A c.2988+1G4A M1101K c.3302 T4A p.Met1101Lys R1162X c.3484C4T p.Arg1162* 3659delC c.3528delC p.Lys1177Serfs*15 M1V c.1 A4G p.? Login to comment

PMID: 26087176 [PubMed] Dupuis A et al: "Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene."

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63 Canadian studies for CF modfier genes 2,492 3,153 43,432 3,596 1,788 2,230 23,397 16,023 3 716 3,438 860 15% (19%) 1,902 2,576 PIP and MIP derivation FEV1 and zBMI modeling MIP calculation following correction of MI variable 23,301 2,413 510 21% (25%) 20% (23%) 13% (15%) Total F508del/others MI prevalence uncorrected (estimated) Missing or incomplete genotype Available for analysis Canadian CF patient registry, born after 1980 US CF patient registry German CF patient registry CF patient registry, North Italy Table 1ߒ Meconium ileus prevalence scores for the most common cystic fibrosis-causing variants p. F508del/other variants Class PIP Canada, (n) MIP, (n) Canada United States Germany Italy HGVS Legacy name c.262_263delTT 394delTT I 0.38 (50) c.3472C>T R1158X I 0.37 (35) c.1558G>T V520F 0.35 (43) c.3484C>T R1162X I 0.34 (135) 0.17 (14) 0.22 (45) c.2012delT 2143delT I 0.33 (13) c.3276C>A or G Y1092X I 0.92 (13) 0.09 (12) 0.33 (55) c.3846G>A W1282X I 1.00 (13) 0.29 (13) 0.32 (442) 0.17 (20) c.1477C>T Q493X I 1.00 (11) 0.19 (11) 0.32 (102) c.3528delC 3659delC I 0.31 (139) c.579ߙ+ߙ1G>T 711ߙ+ߙ1G>T 0.97 (39) 0.30 (38) 0.31 (54) c.178G>T E60X I 0.30 (66) c.1657C>T R553X I 1.00 (16) 0.28 (16) 0.30 (415) 0.24 (107) c.1585-1G>A 1717-1G>A I 1.00 (12) 0.23 (12) 0.29 (367) 0.22 (38) 0.16 (22) c.1766ߙ+ߙ1G>A 1898ߙ+ߙ1G>A 0.29 (139) c.1624G>T G542X I 0.99 (73) 0.31 (72) 0.29 (976) 0.21 (79) 0.22 (33) c.1521_1523delCTT F508del II 0.99 (1292) 0.22 (1260) 0.27 (15391) 0.21 (1910) 0.20 (230) c.1679G>C R560T II 0.27 (123) c.3744delA 3876delA 0.27 (22) c.2128A>T K710X I 0.26 (12) c.1519_1521delATC I507del II 1.00 (20) 0.21 (19) 0.25 (162) c.3909C>G N1303K II 0.98 (40) 0.13 (39) 0.25 (534) 0.23 (80) 0.14 (62) c.489ߙ+ߙ1G>T 621ߙ+ߙ1G>T I 1.00 (90) 0.24 (88) 0.25 (369) 0.21 (11) c.3266G>A W1089X I 0.25 (17) c.1675G>A A559T 0.24 (21) c.988G>T G330X 0.24 (10) c.3773_3774insT 3905insT 0.23 (78) c.2988ߙ+ߙ1G>A 3120ߙ+ߙ1G>A 0.22 (121) c.443T>C I148T;3199del6 1.00 (15) 0.22 (15) c.2052delA 2184delA I 0.21 (89) 0.22 (10) c.2051_2052delAAinsG 2183AA>G 0.20 (73) 0.20 (42) c.948delT 1078delT 0.19 (20) c.1652G>A G551D III 0.96 (54) 0.08 (53) 0.15 (979) 0.09 (84) c.254G>A G85E 0.50 (24) 0.06 (24) 0.14 (137) 0.00 (10) c.3196C>T R1066C 0.14 (42) c.1466C>A S489X 1.00 (14) 0.14 (14) c.3808G>A D1270N 0.13 (19) c.1055G>A R352Q 0.12 (18) c.579ߙ+ߙ5G>A 711ߙ+ߙ5G>A 0.12 (30) c.2175_2176insA 2307insA 0.11 (24) c.349C>T R117C 0.10 (37) c.1040G>C R347P IV 0.18 (11) 0.19 (11) 0.10 (130) 0.02 (56) c.350G>A R117H IV 0.05 (21) 0.00 (21) 0.07 (666) 0.02 (19) c.2657ߙ+ߙ5G>A 2789ߙ+ߙ5G>A V 0.25 (20) 0.00 (20) 0.06 (271) 0.01 (21) c.1040G>A R347H 0.06 (55) c.2988G>A 3120G->A 0.06 (36) c.328G>C D1152H IV 0.06 (124) c.3717ߙ+ߙ12191C>T 3849ߙ+ߙ10kbC>T V 0.07 (14) 0.00 (14) 0.05 (299) 0.01 (42) 0.00 (15) c.1364C>A A455E V 0.16 (45) 0.01 (41) 0.05 (109) c.1000C>T R334W IV 0.18 (11) 0.00 (10) 0.05 (92) c.617T>G L206W 0.06 (18) 0.05 (17) 0.04 (52) c.3302T>A M1101K 0.04 (17) c.200C>T P67L V 0.07 (14) 0.00 (14) Meconium ileus prevalence (MIP) and pancreas insufficiency prevalence (PIP) scores are presented. Login to comment
109 While non-CFTR modifier genes as well as environmental factors largely influence the development and progression of lung disease and nutritional decline,33-36 we demonstrate that the severity of the underlying CFTR genotype Table 2ߒ Meconium ileus prevalence scores and CFTR function CFTR mutation MIP score CFTR function (%wt) High MIP score ߓ V520F 0.38 0.2 ߓ N1303K 0.25 0.5 ߓ F508del 0.27 0.4 ߓ R560T 0.27 0.1 ߓ A559T 0.24 0 ߓ G551D 0.15 1 ߓ G85E 0.14 0.8 ߓ R1066C 0.13 0 Low MIP score ߓ R347P 0.1 0 ߓ R117C 0.1 2.9 ߓ R117H 0.07 33 ߓ R347H 0.06 5 ߓ R334W 0.05 1.3 ߓ A455E 0.05 6 ߓ L206W 0.04 5 ߓ M1101K 0.04 0 ߓ P67L 0.0 8 The table compares meconium ileus prevalence (MIP) scores and measured cystic fibrosis transmembrane conductance regulator (CFTR) function in Fisher rat thyroid determined by VanGoor et al.24 for the major and missense cystic fibrosis-causing variants for which patient group size was ࣙ10 in at least the US group. Login to comment

PMID: 26567541 [PubMed] Bosch B et al: "Searching for a cure for cystic fibrosis. A 25-year quest in a nutshell."

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48 Table 1 CF mutation classes and a potential approach for correcting the defect Mutation class CFTR defect result Mutation type Mutation example Potential therapy Mutation class Specific Aspecific I No full-length CFTR Premature stop codon, Large deletions, Out-of-frame deletions or insertions G524X, W1282X Read-through (e.g. ataluren) RNA correction Gene therapy II Processing defect Missense, amino acid deletion F508del, N1303K, 1507del Corrector III Regulation defect Missense G551D Potentiator (e.g. ivacaftor) IV Decreased conductance Missense R117H Potentiator V Reduced synthesis Missense, change in splicing efficiency 3849+10 kb C࢐G, A455E, 5 T Corrector (e.g. VX-809) Potentiator VI Altered channel stability Nonsense, frameshift 4326 delTC, 4279insA Potentiator Proteastasis inhibitor In class I mutation, no protein reaches the plasma membrane as transcription is halted prematurely in the case of premature stop codons or the protein is non-functional in the case of large deletions or out-of-frame deletions or insertions); in class II mutations, a block in protein folding and trafficking leads to protein degradation in the proteasome; class III mutations lead to a protein with defective channel regulation; in class IV, the CFTR channel has an altered conductance; in class V, the amount of CFTR channels synthetized present at the cell membrane is reduced; class VI mutations lead to a functional but less stable protein in the apical cell membrane. Login to comment

PMID: 7533609 [PubMed] Korst RJ et al: "Gene therapy for the respiratory manifestations of cystic fibrosis."

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99 Alleles G551D, S5491, A455E, and G542X account for 10-20% of the non-L\F508 mutations. Login to comment