ABCMdb

ABCC7 p.Phe693Leu

ClinVar:	c.2079T>G , p.Phe693Leu ? , Uncertain significance c.2077T>C , p.Phe693Leu ? , not provided
CF databases:	c.2077T>C , p.Phe693Leu (CFTR1) ? , This mutation was found on one CF chromosome among 56 Italian CF chromosomes. The patinet is pancreatic insufficient.(Original note Novelli et al. 1992-04-27) NL# 63 2209T/C was also reported as polymorphism by Ferec et al. on 1994-09-16. c.2079T>G , p.Phe693Leu (CFTR1) ? , This mutation was seen on 1 U.S. Hispanic chromosome. ASO analysis revealed that this alteration was not present on 100 non-CF Caucasian chromosomes. This mutation was found in a 17-year old patient with a diagnosis of severe asthma. Sweat testing was high/borderline with values of 86, 58 and 53. Tests were negative for staph and pseudomonas. The mutation was found after sequencing. The 5T splice variant was also found. We are waiting for parental DNA to determine if the 5T is in cis or trans with this mutation.
Predicted by SNAP2:	A: D (80%), C: D (85%), D: D (91%), E: D (91%), G: D (91%), H: D (85%), I: D (80%), K: D (91%), L: N (57%), M: D (80%), N: D (85%), P: D (91%), Q: D (85%), R: D (85%), S: D (85%), T: D (85%), V: D (80%), W: D (85%), Y: D (66%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Many deltaF508 heterozygote neonates with transien... J Med Genet. 2000 Jul;37(7):543-7. Boyne J, Evans S, Pollitt RJ, Taylor CJ, Dalton A
Many deltaF508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation.
J Med Genet. 2000 Jul;37(7):543-7., [PMID:10970190]

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538 These have been reported in patients with presenting phenotypes ranging from "cystic fibrosis" to oligospermia, but there have been too few cases Table 2 Compound heterozygotes detected Domain and mutation type Genotype Exon 1st IRT 2nd IRT Transmembrane, missense F508/P67L 3 129 34* F508/R117H 4 110 21* F508/R117H 4 84 34 F508/R117H 4 95 39 F508/R117H 4 104 40 F508/R117H 4 146 41 F508/R117H 4 104 48* F508/R117H 4 120 53 F508/R117H 4 111 54 F508/R117H 4 175 72* F508/R117L 4 129 70 F508/L967S 15 122 15 F508/F1052V 17b 189 29 F508/R1066H 17b 94 18 Transmembrane, nonsense F508/R75X 3 86 26 F508/R75X 3 171 27 F508/R851X 14a 112 76 Regulatory, missense F508/F693L 13 109 29 Alternate splice site F508/3849+10KB C→T i19 99 26* F508/3849+10KB C→T i19 112 36* None of these samples had the IVS8-5T variant sequence. Login to comment
543 The missense mutation F693L is located in the regulatory domain of CFTR and was first identified in a young girl with F508 on her other allele who was diagnosed with pancreatic insuYcient cystic fibrosis.26 Three subjects had nonsense mutations which are normally associated with severe disease as they introduce a stop codon, leading to truncated, usually inactive, CFTR protein being transcribed. Login to comment

[hide] A combined analysis of the cystic fibrosis transme... Mol Biol Evol. 2001 Sep;18(9):1771-88. Chen JM, Cutler C, Jacques C, Boeuf G, Denamur E, Lecointre G, Mercier B, Cramb G, Ferec C
A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.
Mol Biol Evol. 2001 Sep;18(9):1771-88., [PMID:11504857]

Abstract [show]
Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene. Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480. This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13--coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.

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590 Taking advantage of the previously redefined R domain, a systemic evaluation of the missense mutations occurring in this region was produced, and as a result, some of these mutations, such as F693L, V754M, and T760M, were identified as being likely to represent neutral polymorphisms (Chen, Scotet, and Ferec 2000). Login to comment

[hide] Variant cystic fibrosis phenotypes in the absence ... N Engl J Med. 2002 Aug 8;347(6):401-7. Groman JD, Meyer ME, Wilmott RW, Zeitlin PL, Cutting GR
Variant cystic fibrosis phenotypes in the absence of CFTR mutations.
N Engl J Med. 2002 Aug 8;347(6):401-7., 2002-08-08 [PMID:12167682]

Abstract [show]
BACKGROUND: Cystic fibrosis is a life-limiting autosomal recessive disorder with a highly variable clinical presentation. The classic form involves characteristic findings in the respiratory tract, gastrointestinal tract, male reproductive tract, and sweat glands and is caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene. Nonclassic forms of cystic fibrosis have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. We assessed whether alteration in CFTR function is responsible for the entire spectrum of variant cystic fibrosis phenotypes. METHODS: Extensive genetic analysis of the CFTR gene was performed in 74 patients with nonclassic cystic fibrosis who had been referred by 34 medical centers. We evaluated two families that each included a proband without identified mutations and a sibling with nonclassic cystic fibrosis to determine whether there was linkage to the CFTR locus and to measure the extent of CFTR function in the sweat gland and nasal epithelium. RESULTS: Of the 74 patients studied, 29 had two mutations in the CFTR gene, 15 had one mutation, and 30 had no mutations. A final genotype of two mutations was more common among patients who had been referred after screening for common cystic fibrosis-causing mutations identified one mutation than among those who had been referred after screening had identified no such mutations (26 of 34 patients vs. 3 of 40 patients, P<0.001). Comparison of clinical features and sweat chloride concentrations revealed no significant differences among patients with two, one, or no CFTR mutations. Haplotype analysis in the two families revealed no linkage to CFTR. Although each of the affected siblings had elevated sweat chloride concentrations, measurements of cyclic AMP-mediated ion and fluid transport in the sweat gland and nasal epithelium demonstrated the presence of functional CFTR. CONCLUSIONS: Factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic cystic fibrosis caused by CFTR dysfunction.

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71 MUTATION IDENTIFIED BY SCREENING FOR COMMON MUTATIONS MUTATION IDENTIFIED BY DNA SEQUENCING NO. OF PATIENTS ∆F508 5T* 3 ∆F508 D1152H 2 ∆F508 2789+2insA 2 ∆F508 R117C 2 ∆F508 D110H 1 ∆F508 2789+5G→A 1 ∆F508 P205S 1 ∆F508 L967S 1 ∆F508 I1027T 1 ∆F508 L206W 1 ∆F508 T1053I and 5T 1 ∆F508 V920M and 5T 1 ∆F508 R1070W 1 ∆F508 D579G 1 ∆F508 P67L 1 ∆F508 2811G→T†‡ 1 G85E F191V† 1 R117H G103X and 5T 1 I148T I556V 1 G542X R1162L 1 W1282X D1152H 1 None L138ins and 3272-26 A→G 1 None G463D† and 5T 1 None F693L and 5T 1 ∆F508 None 6 G551D None 1 W1282X None 1 None 5T 4 None 2307insA 1 None L997F 1 None V520I 1 None None 30 in Subject II-2 in Family 1. Login to comment

[hide] Preconception and prenatal cystic fibrosis carrier... Genet Med. 2004 May-Jun;6(3):141-4. Monaghan KG, Bluhm D, Phillips M, Feldman GL
Preconception and prenatal cystic fibrosis carrier screening of African Americans reveals unanticipated frequencies for specific mutations.
Genet Med. 2004 May-Jun;6(3):141-4., [PMID:15354332]

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PURPOSE: It is recommended that cystic fibrosis (CF) carrier screening be made available to African Americans who are either pregnant or planning a pregnancy. We analyzed the carrier and mutant allele frequencies for African Americans undergoing CF carrier screening in our laboratories. METHODS: Between December 2001 and September 2003, we performed carrier screening for 2189 African Americans, testing for at least the 25 recommended mutations. RESULTS: A total of 33 CF carriers were identified. The most common mutations detected were deltaF508, G622D, R117H/7T, and G551D. The G622D allele frequency among African Americans was 0.18%. We did not detect any 3120 + 1G --> A carriers, although 4 were expected (P < 0.05). CONCLUSIONS: When considering only the 25 recommended CF mutations, 1 in 75 African Americans screened in our laboratories were carriers (within the expected range, given a 69% mutation detection rate). The addition of 2 mutations, G622D and Q98R (incidentally identified while screening for ACOG/ACMG mutations), increased the observed carrier frequency to 1 in 66, which is not significantly different from the known African American carrier frequency of 1 in 65. The frequencies of several specific mutations detected were unanticipated, as was the absence of 3120 + 1G --> A carriers. Further studies on African American patients with classic CF are needed to examine the incidence of CF mutations that are not part of the current panel, such as G622D.

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44 Three additional sequence changes, F693L (TTG), Q98R, and P140S(C3T), were incidentally detected by heteroduplex analysis while screening for ACOG/ ACMG CF mutations not included in the test kit used during the time of screening. Login to comment
46 F693L (TTG) and P140S (C3T) are variants of unknown clinical significance. Login to comment
51 R117H has been previously reported at an increased frequency among individuals undergoing carrier screening compared to those with a diagnosis of cystic fibrosis.8 An unexpected result was the lack of 3120ϩ1G3A carriers, although 4 were expected given that this mutation accounts for Ϸ12% of the CF muta- Table 1 Summary of carrier screening results using various methods employed between December 2001 and September 2003 OLA v2.0, heteroduplex analysis (exons 4 and 13) and RFLP analysis (3120ϩ1G3A) OLA v3.0 INNO-LiPA Total screened 818 1274 97 No. of carriers identified 16 14 3 Observed carrier frequency 1/51 1/81 Mutations identified ⌬F508 (6), G622D (3), R117H/7T (3), I148T (3199del6 negative), Q98R, 1898ϩ1G3A, and G551Da ⌬F508 (14), R117H/7T, R553X, and G551D a In addition, 2 persons were positive for F693L (TTG) and 1 was positive for P140S (C3T at 550); both are variants of unknown clinical significance. Login to comment
57 Two mutations, G622D and Q98R, and two variants of unknown clinical significance, F693L (TTG) and P140S (C3T), which are not part of the recommended CF screening panel, were incidentally detected while using heteroduplex analysis to screen for ACOG/ACMG recommended mutations (Table 2). Login to comment
64 This is the case with F693L (TTG), which is currently classified as a CF mutation, reported on one Hispanic CF chromosome in a patient who also had the 5T allele (whether the two mutations were in-trans versus in-cis was not reported).9 However, a different base substitution in the same codon resulting in the same amino acid substitution, F693L (CTT), originally reported as a CF mutation,10 was also reported as a polymorphism.9 This mutation was later shown by functional studies to not affect the CFTR chloride channel activity or protein maturation.11 Therefore, the significance of finding F693 (TTG) in our African American population is not clear. Login to comment

[hide] A novel computational and structural analysis of n... Genomic Med. 2008 Jan;2(1-2):23-32. Epub 2008 May 14. George Priya Doss C, Rajasekaran R, Sudandiradoss C, Ramanathan K, Purohit R, Sethumadhavan R
A novel computational and structural analysis of nsSNPs in CFTR gene.
Genomic Med. 2008 Jan;2(1-2):23-32. Epub 2008 May 14., [PMID:18716917]

Abstract [show]
Single Nucleotide Polymorphisms (SNPs) are being intensively studied to understand the biological basis of complex traits and diseases. The Genetics of human phenotype variation could be understood by knowing the functions of SNPs. In this study using computational methods, we analyzed the genetic variations that can alter the expression and function of the CFTR gene responsible candidate for causing cystic fibrosis. We applied an evolutionary perspective to screen the SNPs using a sequence homology-based SIFT tool, which suggested that 17 nsSNPs (44%) were found to be deleterious. The structure-based approach PolyPhen server suggested that 26 nsSNPS (66%) may disrupt protein function and structure. The PupaSuite tool predicted the phenotypic effect of SNPs on the structure and function of the affected protein. Structure analysis was carried out with the major mutation that occurred in the native protein coded by CFTR gene, and which is at amino acid position F508C for nsSNP with id (rs1800093). The amino acid residues in the native and mutant modeled protein were further analyzed for solvent accessibility, secondary structure and stabilizing residues to check the stability of the proteins. The SNPs were further subjected to iHAP analysis to identify htSNPs, and we report potential candidates for future studies on CFTR mutations.

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125 The nsSNPs which were predicted to be Table 1 List of nsSNPs that were predicted to be deleterious by SIFT and PolyPhen SNPs ID Alleles AA change Tolerance index PSIC rs1800072 G/A V11C 1.00 0.150 rs1800073 C/T R31C 0.18 2.288 rs1800074 A/T D44V 0.01 2.532 rs1800076 G/A R75Q 0.03 1.754 rs1800078 T/C L138P 0.01 2.192 rs35516286 T/C I148T 0.41 1.743 rs1800079 G/A R170H 0.05 1.968 rs1800080 A/G S182G 0.03 1.699 rs1800086 C/G T351S 0.30 1.600 rs1800087 A/C Q353H 0.03 2.093 rs4727853 C/A N417K 1.00 0.015 rs11531593 C/A F433L 0.65 0.694 rs1800089 C/T L467F 0.15 1.568 rs213950 G/A V470M 0.17 1.432 rs1800092 C/A/G I506M 0.00 1.574 rs1801178 A/G I507V 0.38 0.314 rs1800093 T/G F508C 0.00 3.031 rs35032490 A/G K532E 1.00 1.525 rs1800097 G/A V562I 0.13 0.345 rs41290377 G/C G576A 0.33 1.262 rs766874 C/T S605F 0.03 2.147 rs1800099 A/G S654G 0.03 1.611 rs1800100 C/T R668C 0.01 2.654 rs1800101 T/C F693L 0.61 0.895 rs1800103 A/G I807M 0.01 1.554 rs1800106 T/C Y903H 0.52 0.183 rs1800107 G/T S909I 0.10 1.624 rs1800110 T/C L967S 0.07 1.683 rs1800111 G/C L997F 0.24 1.000 rs1800112 T/C I1027T 0.03 1.860 rs1800114 C/T A1067V 0.04 1.542 rs36210737 T/A M1101K 0.05 2.637 rs35813506 G/A R1102K 0.52 1.589 rs1800120 G/T R1162L 0.00 2.038 rs1800123 C/T T1220I 0.22 0.059 rs34911792 T/G S1235R 0.45 1.483 rs11971167 G/A D1270N 0.12 1.739 rs4148725 C/T R1453W 0.00 2.513 Highly deleterious by SIFT and damaging by PolyPhen are indicated as bold deleterious in causing an effect in the structure and function of the protein by SIFT, PolyPhen and Pupasuite correlated well with experimental studies (Tsui 1992; Ghanem et al. 1994; Bienvenu et al. 1998) (Table 3). Login to comment

[hide] Genetic analysis of Rwandan patients with cystic f... Chest. 2009 May;135(5):1233-42. Epub 2008 Nov 18. Mutesa L, Azad AK, Verhaeghe C, Segers K, Vanbellinghen JF, Ngendahayo L, Rusingiza EK, Mutwa PR, Rulisa S, Koulischer L, Cassiman JJ, Cuppens H, Bours V
Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms: identification of novel cystic fibrosis transmembrane conductance regulator and epithelial sodium channel gene variants.
Chest. 2009 May;135(5):1233-42. Epub 2008 Nov 18., [PMID:19017867]

Abstract [show]
BACKGROUND: The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CF transmembrane conductance regulator (CFTR) loss of function and an abnormal interaction between CFTR and the epithelial sodium channel (ENaC). A few patients were described with CF-like symptoms, a single CFTR mutation, and an ENaC mutation. METHODS: To study African patients with CF-like symptoms and to relate the disease to gene mutations of both CFTR and ENaC genes, we collected clinical data and DNA samples from 60 African patients with a CF phenotype. The CFTR gene was first analyzed in all patients by denaturing high-performance liquid chromatography followed by direct sequencing; whereas, the sodium channel non-voltage-gated 1 alpha (SCNN1A), sodium channel non-voltage-gated 1 beta (SCNN1B), and sodium channel non-voltage-gated 1 gamma (SCNN1G) subunits of the ENaC gene were analyzed by sequencing in the five patients who carried only one CF mutation. The frequency of all identified ENaC variants was established in a control group of 200 healthy individuals and in the 55 CF-like patients without any CFTR mutation. RESULTS: Three CFTR mutants, including one previously undescribed missense mutation (p.A204T), and a 5T/7T variant were identified in five patients. ENaC gene sequencing in these five patients detected the following eight ENaC variants: c.72T>C and p.V573I in SCNN1A; p.V348M, p.G442V, c.1473 + 28C>T, and p.T577T in SCNN1B; and p.S212S and c.1176 + 30G>C in SCNN1G. In the 55 CF-like patients without any CFTR mutation, we identified five of these eight ENaC variants, including the frequent p.G442V polymorphism, but we did not detect the presence of the p.V348M, p.T577T, and c.1176 + 30G>C ENaC variants. Moreover, these last three ENaC variants, p.V348M, p.T577T, and c.1176 + 30G>C, were not found in the control group. CONCLUSION: Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations.

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51 We found 14 CFTR variants (Table 2), as follows: two known mutations (p.F693L and c.3120 ϩ 1GϾA); a novel p.A204T missense mutation; and nine sequence polymorphisms; and two previously uncharacterized intronic nucleotide changes, c.3272-32T Ͼ C in the intron 17a and c.4575 ϩ 2GϾA in the 3Ј-untranslated region (UTR). Login to comment
61 The p.F693L mutation was identified in the following two patients: a 13-year-old boy (patient P004) with recurrent respiratory infections, lung colonization by P aeruginosa, GI symptoms, failure to thrive, Table 1-Characteristics of 60 Patients With CF-Like Symptoms Variables Patients (n ϭ 60) % Age, yr Range 2-14 Mean Ϯ SD 5.8 Ϯ 1.7 Sex Male 33 55 Female 27 45 Phenotype Chronic lung disease 39 65 GI symptoms 41 68 Pancreatic insufficiency 19 32 Failure to thrive 23 38 PEM 52 87 Diabetes mellitus 4 7 Nasal polyps 3 5 Sweat chloride test results Positive (Ͼ 60 mmol/L) 37 62 Borderline (40-60 mol/L) 11 18 Normal (Ͻ 40 mmol/L) 9 15 Test not performed 3 5 www.chestjournal.org CHEST / 135 / 5 / MAY, 2009 1235 (c) 2009 American College of Chest Physicians at University of North Carolina on August 8, diabetes mellitus, and PEM; and a 9-year-old girl (patient P038) with mild pulmonary symptoms, GI symptoms, and severe PEM. Login to comment
73 The p.V573I ENaC variant was found in the patient who was heterozygous for the c.3120 ϩ 1GϾA CFTR mutation in combination with the TG12T7 variant, while the p.V348M ENaC mutation was observed in a patient with the p.F693L CFTR mutation. Login to comment
75 The silent polymorphism p.T577T was found in a patient with a p.F693L CFTR mutation, whereas the c.72TϾC was detected in the patient with the novel p.A204T CFTR mutation. Login to comment
91 Table 3-Comparison of Clinical Findings in Five Patients With Identified CFTR and ENaC Mutants* Patient/Sex/Age, yr Phenotype Sweat Test Value, mmol/L CFTR Genotype (͓TG͔mTn) Genotype ENaC Genotype (␣, beta, and ␥ Subunits) P004/M/13 LD, PA, GI, PEM 94 p.F693L/- (TG)10T7/(TG)11T9 p.V348M (beta) p.S212S† (␥) P038/F/9 LD, SA, GI, PEM 124 p.F693L/- (TG)10T7/(TG)10T9 p.T577T (beta) p.G442V† (beta) P007/F/7 LD, PA, GI, PEM 85 c.3120 ϩ 1GϾA/- (TG)11T7/(TG)12T7 p.V573I (␣) p.G442V† (beta) P029/M/2 GI, PI, FT, PEM 77 c.4575 ϩ 2GϾA‡/- (TG)10T7/(TG)11T5 c.1473 ϩ 28CϾT (beta) c.1176 ϩ 30GϾC (␥) P041/F/4 LD, PEM 113 p.A204T/- (TG)10T7/(TG)10T7 c.72 TϾC (␣ 5Ј UTR) p.G442V† (beta) *Tn ϭ poly-T tract; TGm ϭ poly-TG loci; LD ϭ lung disease; PA ϭ P aeruginosa lung colonization; FT ϭ failure to thrive; DM ϭ diabetes mellitus; PI ϭ pancreatic insufficiency; SA ϭ Staphylococcus aureus lung colonization; F ϭ female; M ϭ male. Login to comment
95 CFTR Allele Variants, % (n ϭ 120) p.F693L TϾG at 2211 13 PheϾLeu at 693 2 1.67 c.3120 ϩ 1GϾA GϾA at 3120 ϩ 1 Intron 16 Splicing mutation 1 0.83 p.A204T* GϾA at 742 6a AlaϾThr at 742 1 0.83 c.4575 ϩ 2GϾA GϾA at 4575 ϩ 2 3Ј UTR 1 0.83 p.T854T TϾG at 2694 14a Sequence variation 52 43.33 p.Q1463Q GϾA at 4521 24 Sequence variation 14 11.7 p.M470V AϾG at 1540 10 Sequence variation 13 10.83 c.1898 ϩ 152TϾA TϾA at 1898 ϩ 152 12 Sequence variation 9 7.5 p.P1290P AϾG at 4002 20 Sequence variation 6 5 c.1001 ϩ 11CϾT CϾT at 1001 ϩ 11 Intron 6b Sequence variation 5 4.17 p.E527E AϾG at 1713 10 Sequence variation 3 2.5 c.2752 - 15CϾG CϾG at 2752 - 15 Intron 14a Sequence variation 3 2.5 c.3041 - 71AϾG GϾC at 3041 - 71 Intron 15 Sequence variation 2 1.67 c.3272 - 32TϾC TϾC at 3072 - 32 Intron17a 1 0.83 *Identified novel missense mutation. Login to comment
101 The identified mutations were as follows: (1) a c.3120 ϩ 1GϾA CFTR mutation, frequently observed in African patients and responsible for a splicing defect4; and (2) a p.F693L CFTR missense mutation in two patients with CF-like severe symptoms including recurrent lung disease (the same amino acid change at the same residue has been previously reported23 in an Italian CF patient with severe symptoms; moreover, these two patients carried SCNN1B mutations) [Table 3]; (3) a TG11T5 variant, which can be associated with mild CF signs; and (4) a novel p.A204T CFTR mutation. Login to comment
129 For instance, the two patients with a p.F693L CFTR mutation carried the p.V348M or p.T577T SCNN1B mutation, which were not detected in the control group. Login to comment
47 We found 14 CFTR variants (Table 2), as follows: two known mutations (p.F693L and c.3120 ϩ 1GϾA); a novel p.A204T missense mutation; and nine sequence polymorphisms; and two previously uncharacterized intronic nucleotide changes, c.3272-32T Ͼ C in the intron 17a and c.4575 ϩ 2GϾA in the 3Ј-untranslated region (UTR). Login to comment
57 The p.F693L mutation was identified in the following two patients: a 13-year-old boy (patient P004) with recurrent respiratory infections, lung colonization by P aeruginosa, GI symptoms, failure to thrive, Table 1-Characteristics of 60 Patients With CF-Like Symptoms Variables Patients (n ϭ 60) % Age, yr Range 2-14 Mean Ϯ SD 5.8 Ϯ 1.7 Sex Male 33 55 Female 27 45 Phenotype Chronic lung disease 39 65 GI symptoms 41 68 Pancreatic insufficiency 19 32 Failure to thrive 23 38 PEM 52 87 Diabetes mellitus 4 7 Nasal polyps 3 5 Sweat chloride test results Positive (Ͼ 60 mmol/L) 37 62 Borderline (40-60 mol/L) 11 18 Normal (Ͻ 40 mmol/L) 9 15 Test not performed 3 5 diabetes mellitus, and PEM; and a 9-year-old girl (patient P038) with mild pulmonary symptoms, GI symptoms, and severe PEM. Login to comment
69 The p.V573I ENaC variant was found in the patient who was heterozygous for the c.3120 ϩ 1GϾA CFTR mutation in combination with the TG12T7 variant, while the p.V348M ENaC mutation was observed in a patient with the p.F693L CFTR mutation. Login to comment
71 The silent polymorphism p.T577T was found in a patient with a p.F693L CFTR mutation, whereas the c.72TϾC was detected in the patient with the novel p.A204T CFTR mutation. Login to comment
87 Table 3-Comparison of Clinical Findings in Five Patients With Identified CFTR and ENaC Mutants* Patient/Sex/Age, yr Phenotype Sweat Test Value, mmol/L CFTR Genotype (͓TG͔mTn) Genotype ENaC Genotype (␣, beta, and ␥ Subunits) P004/M/13 LD, PA, GI, PEM 94 p.F693L/- (TG)10T7/(TG)11T9 p.V348M (beta) p.S212S† (␥) P038/F/9 LD, SA, GI, PEM 124 p.F693L/- (TG)10T7/(TG)10T9 p.T577T (beta) p.G442V† (beta) P007/F/7 LD, PA, GI, PEM 85 c.3120 ϩ 1GϾA/- (TG)11T7/(TG)12T7 p.V573I (␣) p.G442V† (beta) P029/M/2 GI, PI, FT, PEM 77 c.4575 ϩ 2GϾA‡/- (TG)10T7/(TG)11T5 c.1473 ϩ 28CϾT (beta) c.1176 ϩ 30GϾC (␥) P041/F/4 LD, PEM 113 p.A204T/- (TG)10T7/(TG)10T7 c.72 TϾC (␣ 5Ј UTR) p.G442V† (beta) *Tn ϭ poly-T tract; TGm ϭ poly-TG loci; LD ϭ lung disease; PA ϭ P aeruginosa lung colonization; FT ϭ failure to thrive; DM ϭ diabetes mellitus; PI ϭ pancreatic insufficiency; SA ϭ Staphylococcus aureus lung colonization; F ϭ female; M ϭ male. Login to comment
97 The identified mutations were as follows: (1) a c.3120 ϩ 1GϾA CFTR mutation, frequently observed in African patients and responsible for a splicing defect4; and (2) a p.F693L CFTR missense mutation in two patients with CF-like severe symptoms including recurrent lung disease (the same amino acid change at the same residue has been previously reported23 in an Italian CF patient with severe symptoms; moreover, these two patients carried SCNN1B mutations) [Table 3]; (3) a TG11T5 variant, which can be associated with mild CF signs; and (4) a novel p.A204T CFTR mutation. Login to comment
125 For instance, the two patients with a p.F693L CFTR mutation carried the p.V348M or p.T577T SCNN1B mutation, which were not detected in the control group. Login to comment

[hide] Characterization of 19 disease-associated missense... Hum Mol Genet. 1998 Oct;7(11):1761-9. Vankeerberghen A, Wei L, Jaspers M, Cassiman JJ, Nilius B, Cuppens H
Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator.
Hum Mol Genet. 1998 Oct;7(11):1761-9., [PMID:9736778]

Abstract [show]
In order to gain a better insight into the structure and function of the regulatory domain (RD) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, 19 RD missense mutations that had been identified in patients were functionally characterized. Nine of these (I601F, L610S, A613T, D614G, I618T, L619S, H620P, G628R and L633P) resulted in aberrant processing. No or a very small number of functional CFTR proteins will therefore appear at the cell membrane in cells expressing these mutants. These mutations were clustered in the N-terminal part of the RD, suggesting that this subdomain has a folding pattern that is very sensitive to amino acid changes. Mutations that caused no aberrant processing were further characterized at the electrophysiological level. First, they were studied at the whole cell level in Xenopus laevis oocytes. Mutants that induced a whole cell current that was significantly different from wild-type CFTR were subsequently analysed at the single channel level in COS1 cells transiently expressing the different mutant and wild-type proteins. Three mutant chloride channels, G622D, R792G and E822K CFTR, were characterized by significantly lower intrinsic chloride channel activities compared with wild-type CFTR. Two mutations, H620Q and A800G, resulted in increased intrinsic chloride transport activities. Finally, T665S and E826K CFTR had single channel properties not significantly different from wild-type CFTR.

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49 Since then, it was found that the F693L mutation is a polymorphism (14,15) and that the I807M polymorphism is associated with congenital bilateral absence of the vas deferens (CBAVD) (our unpublished data). Login to comment
68 Primers used for mutagenesis Primer Sequence I601F (a1933t) 5'-CTA ACA AAA CTA GGT TTT TGG TCA CTT C-3' L610S (t1961c) 5'-CTA AAA TGG AAC ATT CAA AGA AAG CTG-3' A613T (g1969a) 5'-CAT TTA AAG AAA ACT GAC AAA ATA TTA-3' D614G (a1973g) 5'-CAT TTA AAG AAA GCT GGC AAA ATA TTA A-3' I618T (t1985c) 5'-GAC AAA ATA TTA ACT TTG CAT GAA GG-3' L619S (t1988c) 5'-GAC AAA ATA TTA ATT TCG CAT GAA GGT-3' H620P (a1991c) 5'-CAA AAT ATT AAT TTT GCC TGA AGG TAG C-3' H620Q (t1992g) 5'-AAT ATT AAT TTT GCA GGA AGG TAG CAG-3' G622D (g1997a) 5'-TTG CAT GAA GAT AGC AGC TAT TTT TAT G-3' G628R (g2014c) 5'-GCA GCT ATT TTT ATC GGA CAT TTT C-3' L633P (t2030c) 5'-CAT TTT CAG AAC CCC AAA ATC TAC AGC-3' D648V (a2075t) 5'-CTC ATG GGA TGT GTT TCT TTC GAC C-3' T665S (a2125t) 5'-CAA TCC TAA CTG AGT CCT TAC ACC G-3' F693L (t2209c) 5'-CAG ACT GGA GAG CTT GGG GAA AAA AG-3' R766M (g2429t) 5'-GCA CGA AGG ATG CAG TCT GTC CTG-3' R792G (c2506g) 5'-CAG CAT CCA CAG GAA AAG TGT CAC TG-3' A800G (c2531g) 5'-CTG GCC CCT CAG GGA AAC TTG ACT G-3' I807M (a2553g) 5'-CTG AAC TGG ATA TGT ATT CAA GAA GG-3' E822K (g2596a) 5'-GGC TTG GAA ATA AGT AAA GAA ATT AAC G-3' E826K (g2608a) 5'-GAA GAA ATT AAC AAA GAA GAC TTA AAG-3' Selection primer BstBI 5'-CTC TGG GGT CCG GAA TGA CCG AC-3' Two primers were used for each mutagenesis reaction. Login to comment
77 Mutations detected in patients (I601F, L610S, A613T, D614G, I618T, L619S, H620P, H620Q, D622G, G628R, L633P, T665S, F693L, K698R, V754M, R766M, R792G, A800G, I807M, E822K and E826K) are indicated in bold and underlined, the PKA phosphorylation sites by an arrow and the two acidic domains are boxed. Login to comment
85 The remainder (G622D, D648V, F693L, R766M and I807M) did not significantly affect chloride transport ability when compared with wild-type CFTR channels. Login to comment
87 Maturation pattern of RD mutations and their associated phenotype found in patients with the indicated genotype (when the mutation is associated with CF, only the pancreas status is given) Mutation A-form B-form C-form Clinical data Genotype Phenotype Reference I601F + + - I601F/G542X PS M. Schwarz, personal communication L610S + + - Unknown Unknown A613T + + - Unknown Unknown D614G + + - D614G/unknown PI 14 I618T + + - I618T/dF508 PS G.R. Cutting, personal communication L619S + + - L619S/unknown PI B. Tümmler, personal communication H620P + + - H620P/R1158X PS M. Schwarz, personal communication H620Q + + + H620Q/dF508 PI T. Dörk, personal communication G622D + + + G622D/unknown Oligospermia J. Zielenski, personal communication G628R + + - Unknown Unknown L633P + + - L633P/3659delC M. Schwarz, personal communication D648V + + + D648V/3849+10kb C/T PI C. Ferec, personal communication T665S + + + Unknown Unknown F693L + + + F693L/W1282X Healthy C. Ferec; CF Genetic Analysis Consortium R766M + + + R766M/R792G CBAVD D. Glavac, personal communication R792G + + + R766M/R792G CBAVD D. Glavac, personal communication A800G + + + A800G/unknown CBAVD 34 I807M + + + I807M/unknown CBAVD Our observation E822K + + + E822K/unknown PI 35 E826K + + + E826K/unknown Thoracic sarcoidosis C. Bombieri, personal communication +, the protein matures up to that form; -, the protein does not reach the respective maturation step. Login to comment
123 Mutations that did not affect maturation (H620Q, G622D, D648V, T665S, F693L, R766M, R792G, A800G, I807M, E822K and E826K) were subsequently analysedat theelectrophysiologi- cal level. Login to comment
131 The remaining mutations (D648V, T665S, F693L, R766M, I807M and E826K) caused no significant alterations in intrinsic chloride channel activity. Login to comment
132 F693L turned out to be a polymorphism (15), thereby explaining its normal function. Login to comment

[hide] Diagnostic testing by CFTR gene mutation analysis ... J Mol Diagn. 2005 May;7(2):289-99. Schrijver I, Ramalingam S, Sankaran R, Swanson S, Dunlop CL, Keiles S, Moss RB, Oehlert J, Gardner P, Wassman ER, Kammesheidt A
Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.
J Mol Diagn. 2005 May;7(2):289-99., [PMID:15858154]

Abstract [show]
Characterization of CFTR mutations in the U.S. Hispanic population is vital to early diagnosis, genetic counseling, patient-specific treatment, and the understanding of cystic fibrosis (CF) pathogenesis. The mutation spectrum in Hispanics, however, remains poorly defined. A group of 257 self-identified Hispanics with clinical manifestations consistent with CF were studied by temporal temperature gradient electrophoresis and/or DNA sequencing. A total of 183 mutations were identified, including 14 different amino acid-changing novel variants. A significant proportion (78/85) of the different mutations identified would not have been detected by the ACMG/ACOG-recommended 25-mutation screening panel. Over one third of the mutations (27/85) occurred with a relative frequency >1%, which illustrates that the identified mutations are not all rare. This is supported by a comparison with other large CFTR studies. These results underscore the disparity in mutation identification between Caucasians and Hispanics and show utility for comprehensive diagnostic CFTR mutation analysis in this population.

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98 Spectrum of CFTR Sequence Variants in 257 Hispanic Patients Who Underwent Diagnostic DNA Testing for CF Mutations in 257 patients Allele counts of each mutation % of variant alleles (183) % of all alleles tested (514) ACMG/ACOG recommended 25 mutation panel* DeltaF508 53 28.96 10.31 G542X 7 3.83 1.36 R334W 2 1.09 0.39 R553X 2 1.09 0.39 DeltaI507 1 0.55 0.19 1717 - 1 GϾA 1 0.55 0.19 3120 ϩ 1 GϾA 1 0.55 0.19 7 different mutations 67 36.61 13.04 All mutations included ACMG/ACOG 1248 ϩ 1 GϾA 1 0.55 0.19 1249 - 29delAT 1 0.55 0.19 1288insTA1288insTA 1 0.55 0.19 1341 ϩ 80 GϾA1341 ϩ 80 GϾA 1 0.55 0.19 1429del71429del7 1 0.55 0.19 1525 - 42 GϾA1525 - 42 GϾA 1 0.55 0.19 1717 - 1 GϾA 1 0.55 0.19 1717 - 8 GϾA 2 1.09 0.39 1811 ϩ 1 GϾA1811 ϩ 1 GϾA 1 0.55 0.19 2055del9-ϾA 3 1.64 0.58 2105-2117del13insAGAAA 1 0.55 0.19 2215insG 1 0.55 0.19 2585delT2585delT 1 0.55 0.19 2752 - 6 TϾC 1 0.55 0.19 296 ϩ 28 AϾG 1 0.55 0.19 3120 ϩ 1 GϾ A 1 0.55 0.19 3271 ϩ 8 AϾG3271 ϩ 8 AϾG 1 0.55 0.19 3271delGG 1 0.55 0.19 3272 - 26 AϾG 2 1.09 0.39 3876delA 2 1.09 0.39 4016insT 1 0.55 0.19 406 - 1 GϾA 6 3.28 1.17 406 - 6 TϾC 1 0.55 0.19 4374 ϩ 13 A ϾG 1 0.55 0.19 663delT 1 0.55 0.19 874insTACA874insTACA 1 0.55 0.19 A1009T 2 1.09 0.39 A559T 1 0.55 0.19 D1152H 1 0.55 0.19 D1270N 3 1.64 0.58 D1445N 2 1.09 0.39 D836Y 1 0.55 0.19 DeltaF311 1 0.55 0.19 DeltaF508 53 28.96 10.31 DeltaI507 1 0.55 0.19 E116K 2 1.09 0.39 E585X 1 0.55 0.19 E588VE588V 2 1.09 0.39 E831X 1 0.55 0.19 F311L 1 0.55 0.19 F693L 1 0.55 0.19 G1244E 1 0.55 0.19 G542X 7 3.83 1.36 G576A 1 0.55 0.19 H199Y 3 1.64 0.58 I1027T 3 1.64 0.58 I285FI285F 1 0.55 0.19 L206W 3 1.64 0.58 L320V 1 0.55 0.19 L967S 1 0.55 0.19 L997F 3 1.64 0.58 P1372LP1372L 1 0.55 0.19 P205S 1 0.55 0.19 P439SP439S 1 0.55 0.19 Q1313X 1 0.55 0.19 Q890X 2 1.09 0.39 Q98R 1 0.55 0.19 R1066C 1 0.55 0.19 R1066H 1 0.55 0.19 (Table continues) missense variant, I1027T (3212TϾC), in exon 17a.25 Family studies have not been performed to identify which allele carries two mutations. Login to comment
186 Table 3. Continued CFTR mutations Alleles Relative mutation frequency (%) (of 317) G567A 1 Ͻ1 S573C 1 Ͻ1 E585X 1 Ͻ1 T604S 1 Ͻ1 F693L 1 Ͻ1 V754 mol/L 1 Ͻ1 2108delA 1 Ͻ1 2184delA 1 Ͻ1 2215insG 1 Ͻ1 2585delT 1 Ͻ1 2752 - 6TϾC 1 Ͻ1 E831X 1 Ͻ1 D836Y 1 Ͻ1 Y913X 1 Ͻ1 S945L 1 Ͻ1 L967S 1 Ͻ1 3171delC 1 Ͻ1 3199del6 1 Ͻ1 3271 ϩ 8AϾG 1 Ͻ1 R1066H 1 Ͻ1 R1070W 1 Ͻ1 Y1092X 1 Ͻ1 W1098C 1 Ͻ1 3500 - 2AϾT 1 Ͻ1 4016insT 1 Ͻ1 4374 ϩ 13AϾG 1 Ͻ1 D1152H 1 Ͻ1 R1158X 1 Ͻ1 R1162X 1 Ͻ1 W1282X 1 Ͻ1 N1303K 1 Ͻ1 Q1313X 1 Ͻ1 P1372L 1 Ͻ1 R1438W 1 Ͻ1 Total 317 100 Table 3. Login to comment

[hide] Definition of a "functional R domain" of the cysti... Mol Genet Metab. 2000 Sep-Oct;71(1-2):245-9. Chen JM, Scotet V, Ferec C
Definition of a "functional R domain" of the cystic fibrosis transmembrane conductance regulator.
Mol Genet Metab. 2000 Sep-Oct;71(1-2):245-9., [PMID:11001817]

Abstract [show]
The R domain of the cystic fibrosis transmembrane conductance regulator (CFTR) was originally defined as 241 amino acids, encoded by exon 13. Such exon/intron boundaries provide a convenient way to define the R domain, but do not necessarily reflect the corresponding functional domain within CFTR. A two-domain model was later proposed based on a comparison of the R-domain sequences from 10 species. While RD1, the N-terminal third of the R domain is highly conserved, RD2, the large central region of the R domain has less rigid structural requirements. Although this two-domain model was given strong support by recent functional analysis data, the simple observation that two of the four main phosphorylation sites are excluded from RD2 clearly indicates that RD2 still does not satisfy the requirements of a "functional R domain." Nevertheless, knowledge of the CFTR structure and function accumulated over the past decade and reevaluated in the context of a comprehensive sequence comparison of 15 CFTR homologues made it possible to define such a "functional R domain," i.e., amino acids C647 to D836. This definition is validated primarily because it contains all of the important potential consensus phosphorylation sequences. In addition, it includes the highly charged motif from E822 to D836. Finally, it includes all of the deletions/insertions in this region. This definition also aids in understanding the effects of missense mutations occurring within this domain.

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45 For example, F693L, V754M, T760M, and A800G may be assigned as neutral polymorphisms. Login to comment
46 Indeed, F693L was considered to be a neutral polymorphism due to its presence in healthy subjects (unpublished data) and this was confirmed by functional analysis (8). Login to comment

[hide] Variation in a repeat sequence determines whether ... Am J Hum Genet. 2004 Jan;74(1):176-9. Epub 2003 Dec 18. Groman JD, Hefferon TW, Casals T, Bassas L, Estivill X, Des Georges M, Guittard C, Koudova M, Fallin MD, Nemeth K, Fekete G, Kadasi L, Friedman K, Schwarz M, Bombieri C, Pignatti PF, Kanavakis E, Tzetis M, Schwartz M, Novelli G, D'Apice MR, Sobczynska-Tomaszewska A, Bal J, Stuhrmann M, Macek M Jr, Claustres M, Cutting GR
Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.
Am J Hum Genet. 2004 Jan;74(1):176-9. Epub 2003 Dec 18., [PMID:14685937]

Abstract [show]
An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

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40 Nine patients with nonclassic CF were referred from CF care centers in the United States and were confirmed to have a 5T in trans with one of the following CFTR mutations: DF508 (6), 2814insA (1), G463D (1), or F693L (1). Login to comment

[hide] A mutation in the beta-subunit of ENaC identified ... Am J Physiol Lung Cell Mol Physiol. 2013 Jan 1;304(1):L43-55. doi: 10.1152/ajplung.00093.2012. Epub 2012 Oct 19. Rauh R, Soell D, Haerteis S, Diakov A, Nesterov V, Krueger B, Sticht H, Korbmacher C
A mutation in the beta-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect.
Am J Physiol Lung Cell Mol Physiol. 2013 Jan 1;304(1):L43-55. doi: 10.1152/ajplung.00093.2012. Epub 2012 Oct 19., [PMID:23087020]

Abstract [show]
In some patients with atypical cystic fibrosis (CF), only one allele of the CF transmembrane conductance regulator (CFTR) gene is affected. Mutations of the epithelial sodium channel (ENaC) may contribute to the pathophysiology of the disease in these patients. To functionally characterize a mutation in the beta-subunit of ENaC (betaV348M) recently identified in a patient with severe CF-like symptoms (Mutesa et al. 2009), we expressed wild-type (wt) alphabetagammaENaC or mutant alphabetaV348MgammaENaC in Xenopus laevis oocytes. The betaV348M mutation stimulated amiloride-sensitive whole-cell current (DeltaI(ami)) by approximately 40% but had no effect on surface expression or single-channel conductance of ENaC. Instead the mutation increased channel open probability (P(o)). Proteolytic activation of mutant ENaC by chymotrypsin was reduced compared with that of wt ENaC ( approximately 3.0-fold vs. approximately 4.2-fold), which is consistent with the increased baseline P(o) of mutant ENaC. Similarly, the ENaC activator S3969 stimulated mutant ENaC currents to a lesser degree (by approximately 2.6-fold) than wt ENaC currents (by approximately 3.5-fold). The gain-of-function effect of the betaV348M mutation was confirmed by whole-cell current measurements in HEK293 cells transiently transfected with wt or mutant ENaC. Computational channel modeling in combination with functional expression of different betaV348 mutants in oocytes suggests that the betaV348M mutation increases channel P(o) by destabilizing the closed channel state. Our findings indicate that the gain-of-function effect of the betaV348M mutation may contribute to CF pathophysiology by inappropriately increasing sodium and fluid absorption in the respiratory tract.

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377 In this context, it is of interest that the patient reported by Mutesa et al. (39) was compound heterozygous for the betaV348M mutation and a F693L-CFTR mutation. Login to comment
378 The F693L-CFTR mutation was described as a polymorphism that, compared with wild-type CFTR, did not affect channel maturation in COS1 cells or chloride transport ability in oocytes (57). Login to comment
379 Therefore, it seems unlikely that the F693L-CFTR mutation alone is sufficient to cause the disease. Login to comment