ABCMdb

ABCC7 p.Ile1234Val

ClinVar:	c.3700A>G , p.Ile1234Val D , Pathogenic
CF databases:	c.3700A>G , p.Ile1234Val D , CF-causing ; CFTR1: This mutation was detected through the formation of an unusual DdeI restriction pattern of PCR products obtained with primers 19-i5/19-i3. Direct sequencing of PCR products proved a A->G subsitution at nucleotide 3833. This results in an isoleucine to valine substitution at the codon 1234 and creates a new DdeI restriction site. The patient is carrying a [delta]F508 mutation on the other CF chromosome. This nucleotide change was not found in 120 non-[delta]F508 CF chromosomes.
Predicted by SNAP2:	A: D (85%), C: D (85%), D: D (95%), E: D (95%), F: D (66%), G: D (95%), H: D (95%), K: D (95%), L: D (66%), M: D (85%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: N (93%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] Geographic distribution of cystic fibrosis transme... Ann Trop Paediatr. 1999 Mar;19(1):69-73. Banjar H, Kambouris M, Meyer BF, al-Mehaidib A, Mogarri I
Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia.
Ann Trop Paediatr. 1999 Mar;19(1):69-73., [PMID:10605524]

Abstract [show]
A descriptive study was undertaken to characterize the cystic fibrosis transmembrane regulator gene mutations (CFTR) in the Saudi Arabian cystic fibrosis (CF) population in relation to clinical presentation and demographic and ethnic origin. During the period October 1992 to September 1997, 70 patients from 46 families were diagnosed as having CF, based on a typical clinical picture and sweat chloride levels > 60 mmol/l and were screened for CFTR mutations. Twelve mutations were identified in 34 families, which constitutes 70% of the CF alleles in the study group. Pancreatic insufficiency (PI) was found in the following mutations: 1548delG in exon 10 (15%) which occurred mainly in native Saudi patients in the central province; 3120 + 1G-->A in intron 16 (10%) and H139L in exon 4 (7%), found mainly in native Saudis from the eastern province; delta F508 mutation (13%) which occurred mainly in expatriates of Middle Eastern origin from different provinces; L117X in exon 19 (2%); G115X in exon 4 (2%); 711 + 1G-->A in intron 5 (2%); N 1303K in exon 21 (2%) and 425del42 in exon 4 (1%); I1234V in exon 19 (13%) with a predominance of nasal polyps and a variable degree of PI and lung disease; R553X in exon 11 (1%), with electrolyte imbalance; and S549R in 11 (2%) with pancreatic sufficiency and minimal pulmonary disease. The clinical picture did not differ significantly between patients of different ethnic origins with the same CFTR mutation.

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No. Sentence Comment
4 Pancreatic insuf® ciency (PI) was found in the following mutations: 1548delG in exon 10 (15%) which occurred mainly in native Saudi patients in the central province; 3120 1 1G ® A in intron 16 (10%) and H139L in exon 4 (7%), found mainly in native Saudis from the eastern province; D F508 mutation (13%) which occurred mainly in expatriates of Middle Eastern origin from different provinces; L117X in exon 19 (2%); G115X in exon 4 (2%); 7111 1G ® A in intron 5 (2%); N 1303K in exon 21(2%) and 425del42 in exon 4 (1%); I1234V in exon 19 (13%) with a predominance of nasal polyps and a variable degree of PI and lung disease; R553X in exon 11 (1%), with electrolyte imbalance; and S549R in 11 (2%) with pancreatic suf® ciency and minimal pulmonary disease. Login to comment
31 1 Sa S 1 1 N1303K/3120 1 1G® A* 1 NonSa W 1 1 R553X/31201 1G ® A* 1 NonSa W 1 1 7 Total 9 Total 9 Total Exon 19 I1234V 4/1/1 Sa C/W/S 12 13 NP Exon 21 N1303K/3120 1 1G® A* 1 NonSa W 1 1 N1303K/1548delG* 1 Sa E 1 1 2 Total 2 Total 2 Total a All mutations are homozygous except if otherwise indicated; ? Login to comment
41 I1234V was found in six (13%) native Saudi families, four of them from Central Province. Login to comment
50 The most common Saudi mutations are 1548delG, which constitutes 15% of the total alleles, and I1234V (13%), coming mainly from the Central Province, while 1G ® A (10%) and H139L (7%) were mainly from Eastern Province. Login to comment

[hide] Identification of novel mutations in Arabs with cy... Eur J Pediatr. 2000 May;159(5):303-9. Kambouris M, Banjar H, Moggari I, Nazer H, Al-Hamed M, Meyer BF
Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations.
Eur J Pediatr. 2000 May;159(5):303-9., [PMID:10834512]

Abstract [show]
The cystic fibrosis transmembrane regulator (CFTR) gene in Arab patients with cystic fibrosis (CF) (sweat chloride > 60 mmol/l) from 61 unrelated families was screened for mutations in exons 3, 4, 5, 7, 10, 11, 16 and 19 and for mutations W1282X, N1303K and 3,849 + 10kbC --> T. Eight novel mutations were identified. These are: in exon 4: a) 425del42 (an in-frame 42 bp deletion that removes 14 amino acids and causes Gln98 --> His at the point of deletion), b) 475G --> T (Glu115 --> Stop) and c) 548A --> T (His139 --> Leu); in intron 5,711 + 1G --> A (splice site mutation); in exon 10, 1548delG (deletion of a "G" nucleotide causing a frameshift mutation that alters the amino acid sequence at residue 473 and results in translation termination at residue 526); in exon 11, a) 1729T --> C (Ph533E --> Leu) and b) 1,811 + 2 (splice site mutation) and finally in exon 19,3361A --> T (Lys1177 --> Stop). All mutations were detected by heteroduplex analysis and identified by sequencing. Of more than 850 known CFTR mutations, only 9 were encountered. The comparative frequencies of the most common mutations are: 1548delG> 1123V = deltaF508 = 3,120 + 1G --> A > H139L. Screening for these five mutations identifies 60% of the CF alleles in Arab populations. The novel mutation 1548delG is the most frequent (17%) among Arabs. CONCLUSION: Novel Arab-specific mutations were identified in the CFTR gene underlying cystic fibrosis. As a result of this study, the CFTR mutation detection rate among Arabs with cystic fibrosis is now comparable to that of other populations.

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63 Of more than 850 known CFTR mutations (http:// www.genet.sickkids.on.ca/cftr-cgi-bin/Mutation Table), only 9 were encountered in this study: R75X, A141D, 1249G ® A, DF508, S549R, R553X, 3120 + 1G ® A, I1234V and N1303K. Login to comment
80 These are: DF508, the most common mutation in Caucasians, 3120 + 1G ® A, the most common mutation in Africans and I1234V which has been reported previously as a ``familial'' mutation in the South of France [3]. Login to comment
109 1 (private mutation) 475G ® T G115X ± protein truncation 1 2 1a [I1234V] 1 Total: 2 2.5% 536C ® T A141D 1 2 (private mutation) 548A ® T H139L 3 6 1a [S549R] 1 Total: 4 6% Exon 5 711 + 1G ® A Splice site 1 2 1a [?] Login to comment
115 1 Total: 8 11% Exon 19 3661A ® T K1177X ± protein truncation 1 2 (private mutation) 3832A ® G I1234V 7 14 1a [G115X] 1 Total: 8 12.5% Exon 21 4041C ® G N1303K 1a [1548delG] 1 1a [3120 + 1G ® A] 1 Total: 2 1.5% Undetected 11 22 1a [425del42] 1 1a [711 + 1G ® A] 1 2a [1548delG] 2 2a [DF508] 2 1a [F533L] 1 1a [1249 + 1G ® A] 1 1a [3120 + 1G ® A] 1 Total: 20 25% a Indicates a compound heterozygous family. Login to comment

[hide] DHPLC screening of cystic fibrosis gene mutations. Hum Mutat. 2002 Apr;19(4):374-83. Ravnik-Glavac M, Atkinson A, Glavac D, Dean M
DHPLC screening of cystic fibrosis gene mutations.
Hum Mutat. 2002 Apr;19(4):374-83., [PMID:11933191]

Abstract [show]
Denaturing high performance liquid chromatography (DHPLC) using ion-pairing reverse phase chromatography (IPRPC) columns is a technique for the screening of gene mutations. In order to evaluate the potential utility of this assay method in a clinical laboratory setting, we subjected the PCR products of 73 CF patients known to bear CFTR mutations to this analytic technique. We used thermal denaturation profile parameters specified by the MELT program tool, made available by Stanford University. Using this strategy, we determined an initial analytic sensitivity of 90.4% for any of 73 known CFTR mutations. Most of the mutations not detected by DHPLC under these conditions are alpha-substitutions. This information may eventually help to improve the MELT algorithm. Increasing column denaturation temperatures for one or two degrees above those recommended by the MELT program allowed 100% detection of CFTR mutations tested. By comparing DHPLC methodology used in this study with the recently reported study based on Wavemaker 3.4.4 software (Transgenomic, Omaha, NE) [Le Marechal et al., 2001) and with previous SSCP analysis of CFTR mutations [Ravnik-Glavac et al., 1994] we emphasized differences and similarities in order to refine the DHPLC system and discuss the relationship to the alternative approaches. We conclude that the DHPLC method, under optimized conditions, is highly accurate, rapid, and efficient in detecting mutations in the CFTR gene and may find high utility in screening individuals for CFTR mutations. Hum Mutat 19:374-383, 2002. Published 2002 Wiley-Liss, Inc.

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42 The following mutations have been studied: exon 3: W57G, R74W, R75Q, G85E, 394delTT, 405+ 1G>A; exon 4: E92X, P99L, 441delA, 444delA, 457TAT>G, D110H, R117C, R117H, A120T, 541delC, 544delCA, Q151X, 621+1G>T, 662- 2A>C; exon 7: 1078delT, F331L, R334W, I336K, R347C, R347P, A349V, R352Q, 1221delCT; exon 10: S492F, Q493X, 1609delCA, deltaI507, deltaF508; exon 11: G542X, S549N, G551D, R553X, A559T, R560K, R560T; exon 13: K716X, Q685X, G628R, L719X; exon 17b: H1054D, G1061R, 3320ins5, R1066H, R1066L, R1070Q, 3359delCT, L1077P, H1085R, Y1092X; exon 19: R1162X, 3659delC, 3662delA, 3667del4, 3737delA, I1234V, S1235R, 3849G>A; exon 20: 3860ins31,S1255X,3898insC,3905insT,D1270N, W1282X, Q1291R; and exon 21: N1303H, N1303K, W1316X. Login to comment

[hide] Cystic fibrosis: a worldwide analysis of CFTR muta... Hum Mutat. 2002 Jun;19(6):575-606. Bobadilla JL, Macek M Jr, Fine JP, Farrell PM
Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.
Hum Mutat. 2002 Jun;19(6):575-606., [PMID:12007216]

Abstract [show]
Although there have been numerous reports from around the world of mutations in the gene of chromosome 7 known as CFTR (cystic fibrosis transmembrane conductance regulator), little attention has been given to integrating these mutant alleles into a global understanding of the population molecular genetics associated with cystic fibrosis (CF). We determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort designed to: 1) increase our understanding of ancestry-genotype relationships, 2) compare mutational arrays with disease incidence, and 3) gain insight for decisions regarding screening program enhancement through CFTR multi-mutational analyses. Information on all mutations that have been published since the identification and cloning of the CFTR gene's most common allele, DeltaF508 (or F508del), was reviewed and integrated into a centralized database. The data were then sorted and regional CFTR arrays were determined using mutations that appeared in a given region with a frequency of 0.5% or greater. Final analyses were based on 72,431 CF chromosomes, using data compiled from over 100 original papers, and over 80 regions from around the world, including all nations where CF has been studied using analytical molecular genetics. Initial results confirmed wide mutational heterogeneity throughout the world; however, characterization of the most common mutations across most populations was possible. We also examined CF incidence, DeltaF508 frequency, and regional mutational heterogeneity in a subset of populations. Data for these analyses were filtered for reliability and methodological strength before being incorporated into the final analysis. Statistical assessment of these variables revealed that there is a significant positive correlation between DeltaF508 frequency and the CF incidence levels of regional populations. Regional analyses were also performed to search for trends in the distribution of CFTR mutations across migrant and related populations; this led to clarification of ancestry-genotype patterns that can be used to design CFTR multi-mutation panels for CF screening programs. From comprehensive assessment of these data, we offer recommendations that multiple CFTR alleles should eventually be included to increase the sensitivity of newborn screening programs employing two-tier testing with trypsinogen and DNA analysis.

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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
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
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

[hide] Spatial and temporal distribution of cystic fibros... Hum Genet. 2002 Sep;111(3):247-54. Epub 2002 Aug 1. Scotet V, Gillet D, Dugueperoux I, Audrezet MP, Bellis G, Garnier B, Roussey M, Rault G, Parent P, De Braekeleer M, Ferec C
Spatial and temporal distribution of cystic fibrosis and of its mutations in Brittany, France: a retrospective study from 1960.
Hum Genet. 2002 Sep;111(3):247-54. Epub 2002 Aug 1., [PMID:12215837]

Abstract [show]
Cystic fibrosis (CF) is the most common severe inherited disorder that affects children in Caucasian populations. The aim of this study was to define the spatial and temporal distribution of CF and its mutations in Brittany (western France) where the frequency of the disease is high. We retrospectively registered all CF patients born in Brittany since 1960 by cross-checking various data sources (e.g. medical care centres, genetics laboratories, hospital archives). Councils were contacted so that the place of residence of patients at birth could be determined. Moreover, the spectrum of CF transmembrane conductance regulator (CFTR) mutations and their spatial distribution across Brittany were determined. A total of 520 patients was registered in this study. The incidence of CF was assessed according to administrative (department, district) and diocesan divisions of Brittany and its evolution analysed over four decades. The incidence of CF was 1/2630, with a west/east gradient that was confirmed over time (Finistere: 1/2071 vs Ille-et-Vilaine: 1/3286). At present, the incidence of CF is decreasing, mainly as a result of prenatal diagnosis. An excellent mutation detection rate of 99.7% was obtained. Western Brittany presented a specific spectrum of mutations: 1078delT (9.4% of mutated alleles in the diocese of Cornouaille), G551D (7.7% in the diocese of Leon), 4005+1G-->A (2.9% in Cornouaille) and W846X (1.5% in western Brittany). On the other hand, the eastern region showed a spectrum more similar to the overall picture in France as a whole. This study enabled a precise measurement of the incidence of CF in Brittany to be obtained. The high frequency of the CFTR mutated alleles may result from founder effects and genetic drifts. Moreover, the study brings together the regional specificities of the CFTR gene and highlights disparities that exist in this part of France, both in incidence and in mutation distribution. These are attributable to different degrees of isolation and of population movements between the eastern and western parts of the region. Given that this is the first time that such a detailed study of the CFTR gene has been performed on a large population, this heightened knowledge of the epidemiology of CF in Brittany should provide a basis for the improvement of diagnostic strategies and refinement of genetic counselling.

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118 His genotype was ∆F508/∆F508 Mutation Exon Basse-Bretagne Haute-Bretagne Brittanya ∆F508 10 446 75.6% 224 73.7% 672 75.0% 1078delT 7 31 5.3% 3 1.0% 34 3.8% G551D 11 21 3.6% 12 3.9% 33 3.7% N1303K 21 3 0.5% 9 3.0% 12 1.3% W846X 14a 9 1.5% 1 0.3% 10 1.1% 2789+5G→A 14b 3 0.5% 6 2.0% 9 1.0% 1717-1G→A 11 5 0.8% 3 1.0% 8 0.9% Y1092X 17b 1 0.2% 6 2.0% 7 0.8% 4005+1G→A 20 6 1.0% 1 0.3% 7 0.8% E60X 3 3 0.5% 3 1.0% 6 0.7% 621+1G→T 4 3 0.5% 3 1.0% 6 0.7% R347H 7 6 1.0% 0 0.0% 6 0.7% S492F 10 2 0.3% 3 1.0% 5 0.6% G542X 11 4 0.7% 1 0.3% 5 0.6% 3272-26A→G 17b 2 0.3% 3 1.0% 5 0.6% R117H 4 3 0.5% 1 0.3% 4 0.4% G91R 3 3 0.5% 0 0.0% 3 0.3% ∆I507 10 1 0.2% 2 0.7% 3 0.3% R553X 11 3 0.5% 0 0.0% 3 0.3% W1282X 20 2 0.3% 1 0.3% 3 0.3% A72D 3 0 0.0% 2 0.7% 2 0.2% G85E 3 0 0.0% 2 0.7% 2 0.2% F311L 7 0 0.0% 2 0.7% 2 0.2% 1221delCT 7 2 0.3% 0 0.0% 2 0.2% R560K 11 0 0.0% 2 0.7% 2 0.2% 2622+1G→A 13 2 0.3% 0 0.0% 2 0.2% S945L 15 0 0.0% 2 0.7% 2 0.2% I1234V 19 2 0.3% 0 0.0% 2 0.2% G1249R 20 2 0.3% 0 0.0% 2 0.2% 3905insT 20 2 0.3% 0 0.0% 2 0.2% Unidentified - 3 0.5% 0 0.0% 3 0.3% Total - 590 65.7% 304 34.3% 896 100% IVS17bTA, IVS17bCA) of Irish, Scottish, English, Breton and Czech subjects who were carriers of this mutation, and showed that all these alleles carried a unique haplotype (16-7-17), testifying to the Celtic origin of this mutation (Cashman et al. 1995). Login to comment

[hide] Cystic fibrosis transmembrane regulator gene mutat... J Trop Pediatr. 2002 Dec;48(6):348-50. Eskandarani HA
Cystic fibrosis transmembrane regulator gene mutations in Bahrain.
J Trop Pediatr. 2002 Dec;48(6):348-50., [PMID:12521276]

Abstract [show]
A genotypic study was undertaken to characterize the cystic fibrosis transmembrane regulator gene mutations (CFTR) in the Bahraini cystic fibrosis (CF) population using a polymerase chain reaction-based direct gene test to search for 15 common CF mutations amongst Arabs. During the period October 2000 to May 2001, 19 patients (12 males and seven females; aged at time of study between 4 months and 14 years with a mean age of 5.4 +/- 4.3 years) from 13 families were recruited in the study. Patients were diagnosed as having CF, based on a typical clinical picture and sweat chloride levels > 60 mmol/l and were screened for CFTR mutations. The rate of consanguinity among the families was 77 per cent. Eight mutations were detected in 21 of the 26 alleles examined. The overall detection rate was approximately 81 per cent. The allele frequency of the eight mutations was estimated to be approximately 73 per cent. There was no specific phenotypic pattern that correlated with a specific genotype. All families except two were of Bahraini origin. Of the eight mutations detected, four were common among Bahrainis (2043delG > 548A --> T > 4041C --> G = deltaF508, in order of decreasing frequency), accounting for 66 per cent of the Bahraini CF alleles. However, we also detected four different heterozygous mutations, namely: 1161delC, 1756G -->T, 3120 + 1G --> A, and 3661A --> T, accounting for 16 per cent of the Bahraini CF alleles.

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25 Isolation and PCR amplification of genomic DNA Genomic DNA was extracted from leucocytes according to standard procedures.10 PCR amplification of DNA was performed by preparation of a 50-µl reaction mixture that contained appropriate primers using standard protocols.4 Mutation analysis All patients were screened for 15 common mutations amongst Arabs by restriction enzyme digestion analysis with appropriate enzymes according to specific protocols4,5 and/or using the amplification refractory mutation system (ARMS-PCR) technique.11 These mutations were: 406-2A→G (intron 3), 425del42 (exon 4), 475G→T (exon 4), 548A→T (exon 4), 1161delC (exon 7), 1548delG (exon10), F508 (exon 10), G542X (exon 11), 2043delG (exon 13), 3120+1G→A (intron 16), 3661A→T (exon 19), 3849+10KbC→T (intron 19), I1234V (exon 19), W1282X (exon 20), and N1303K (exon 21). Login to comment
51 However, mutation I1234V, which is specifically the most common mutation amongst neighboring Qatari patients8 and is generally a common mutation in Arab patients,5 was not detected in Bahraini patients. Login to comment

[hide] Cystic fibrosis mutation I1234V in a Qatari lady. J Trop Pediatr. 2003 Feb;49(1):54-5. Wahab AA
Cystic fibrosis mutation I1234V in a Qatari lady.
J Trop Pediatr. 2003 Feb;49(1):54-5., [PMID:12630722]

Abstract [show]
We describe a late diagnosis of cystic fibrosis (CF) in a multiparous Qatari lady, in whom the main presenting symptoms were those of chronic lung disease. Genetic analysis showed that the patient has a homozygous mutation I1234V in the cystic fibrosis transmembrane conductance regulator gene. This suggests that this mutation has a variable expression of clinical severity and long survival.

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2 However, a wide range of severity is seen, with case reports documenting affected individuals in their sixth and seventh decades.3,4 Similarly, differences are seen in the rate at which respiratory function declines.5 We describe the phenotype of a multiparous Qatari lady with late CF diagnosis carrying a pathogenic mutation I1234V causing CF in both CFTR alleles which, to our knowledge, is the oldest case published. Login to comment
17 Her genotype showed a homozygous I1234V mutation in exon 19 in both alleles of the CFTR gene. Login to comment
22 First, CF was suspected based on the patient`s clinical history of recurrent chest infections with Case Reports Cystic Fibrosis Mutation I1234V in a Qatari Lady by A. Abdul Wahab Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar Summary We describe a late diagnosis of cystic fibrosis (CF) in a multiparous Qatari lady, in whom the main presenting symptoms were those of chronic lung disease. Login to comment
23 Genetic analysis showed that the patient has a homozygous mutation I1234V in the cystic fibrosis transmembrane conductance regulator gene. Login to comment
28 Third, the case draws attention to variable presentation of CF mutation I1234V of the CFTR gene. Login to comment
29 CF mutation I1234V is a missense mutation, replacing adenine with guanine at the nucleotide 3832 of CFTR gene in exon 19 and this results in the replacement of an isoleucine by a valine at codon 1234. Login to comment
30 CF mutation I1234V was first described in the south of France9 in 1992 in a 12-year-old carrying a ∆ F508 allele on the maternally inherited CF chromosome who presented only with severe pulmonary involvement. Login to comment
31 Another study by El-Hartih, et al.,10 reported homozygous I1234V mutation in two sisters from an Arab tribe who presented with failure to thrive and recurrent diarrhoea. Login to comment
33 A recent study from our institution reported homozygous I1234V mutation in 29 subjects (17 families) belonging to the same tribe with ages ranging from 8 months to 21 years. Login to comment
34 They presented with a variable degree of pulmonary disease, pancreatic insufficiency and electrolyte imbalance.11 In conclusion, CF mutation I1234V has variable age presentation from early infancy to adulthood with variable clinical presentation. Login to comment

[hide] Comparison of the CFTR mutation spectrum in three ... Hum Mutat. 2003 Jul;22(1):105. Scotet V, Barton DE, Watson JB, Audrezet MP, McDevitt T, McQuaid S, Shortt C, De Braekeleer M, Ferec C, Le Marechal C
Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland.
Hum Mutat. 2003 Jul;22(1):105., [PMID:12815607]

Abstract [show]
This study aims to compare the spectrum of the mutations identified in the gene responsible for cystic fibrosis in three cohorts of patients of Celtic origin from Brittany and Ireland. It included 389 patients from Brittany, 631 from Dublin and 139 from Cork. The CFTR gene analysis relied on the detection of the most common mutations, followed by a complete gene scanning using DGGE or D-HPLC. High mutation detection rates were obtained in each cohort: 99.6%, 96.8%, and 96.0% respectively. A high frequency of the c.1652_1655 del3 mutation (F508del: 74.8% to 81.3%) and of the "Celtic" mutation (c.1784G>A (G551D): 3.7% to 9.7%) was observed in each population. Apart from this, the mutation spectrums differed. In Brittany, the most common abnormalities were: c.1078delT (3.6%), c.4041C>G (N1303K: 1.4%), c.2670G>A (W846X(2): 1.0%) and c.1717-1G>A (1.0%), whereas in the cohort of Dublin, the main mutations were: c.482G>A (R117H: 3.0%), c.1811G>C (R560T: 2.4%) and c.621+1G>T (1.7%). Finally, in the Cork area, only the c.482G>A mutation (R117H) reached a frequency of 1%. Two previously-unreported mutations were identified in the Dublin cohort: c.2623-2A>G and c.3446T>G (M1105R). This collaborative study highlights the similarities of the CFTR alleles in the Breton and Irish populations, but also the disparities that exist between these populations, despite their common origin. Each population has its own history, with its mixture of founder effects and genetic drifts, which are at the origin of the current mutation distribution. The molecular study of the CFTR gene provides new tools for retracing European populations' histories.

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64 Spectrum of the CFTR Mutations Identified in the Cohorts from Brittany, Dublin Centre, and Cork Area Nucleotide Amino acid change * change Exon Number Frequency Number Frequency Number Frequency 211delG 2 1 0.1% 310G>T E60X 3 5 0.6% 4 0.3% 347C>A A72D 3 1 0.1% 368G>A W79X 3 1 0.1% 386G>A G85E 3 2 0.3% 3 0.2% 403G>A G91R 3 2 0.3% 482G>A R117H 4 4 0.5% 38 3.0% 4 1.4% 498T>A Y122X 4 1 0.1% 574delA 4 1 0.1% 577G>A G149R 4 1 0.1% 621+1G>T int 4 5 0.6% 21 1.7% 790C>T Q220X 6a 1 0.1% 875+1G>C int 6a 1 0.4% 905delG 6b 1 0.1% 1065C>G F311L 7 2 0.3% 1078delT 7 28 3.6% 1132C>T R334W 7 1 0.1% 1172G>A R347H 7 5 0.6% 1172G>T R347L 7 1 0.1% 1172G>C R347P 7 1 0.1% 1187G>A R352Q 7 3 0.2% 2 0.7% 1208A>G Q359R 7 1 0.1% 1154insTC 7 2 0.2% 1221delCT 7 2 0.3% 1248+1G>A int 7 1 0.1% 1249-27delTA int 7 1 0.4% 1334G>A W401X 8 1 0.1% 1461ins4 9 5 0.4% 1471delA 9 2 0.2% 1607C>T S492F 10 2 0.3% 1609C>T Q493X 10 1 0.1% 1648_1653delATC I507del 10 3 0.4% 10 0.8% 1 0.4% 1652_1655del 3 bp F508del 10 582 74.8% 966 76.5% 226 81.3% 1690G>T V520F 10 4 0.3% 1717-1G>A int 10 8 1.0% 9 0.7% 1756G>T G542X 11 5 0.6% 8 0.6% 1779T>G S549R 11 1 0.1% 1784G>A G551D 11 29 3.7% 82 6.5% 27 9.7% 1789C>G R553G 11 1 0.1% 1789C>T R553X 11 3 0.4% 1 0.1% 1806delA 11 1 0.1% 1811G>A R560K 11 2 0.3% 1811G>C R560T 11 30 2.4% 2 0.7% 1819T>A Y563N 12 1 0.1% 1853C>A P574H 12 1 0.1% 1898+1G>A int 12 1 0.1% 2184delA 13 1 0.1% 1 0.1% 2184insA 13 1 0.1% 2622+1G>A int 13 1 0.1% 2 0.2% 2622+1G>T int 13 1 0.1% 2623-2A>G ** int 13 1 0.1% 2670G>A W846X2 14a 8 1.0% 2752-1G>T int 14a 1 0.1% 2752-26A>G int 14a 2 0.2% 2789+5G>A int 14b 6 0.8% 2966C>T S945L 15 2 0.3% 3007delG 15 4 0.3% 3040G>C G970R 15 1 0.1% 3062C>T S977F 16 1 0.1% 3120+1G>A int 16 1 0.1% 3272-26A>G int 17a 4 0.5% 2 0.2% 2 0.7% 3320dupli(CTATG) 17b 1 0.1% 3329G>A R1066H 17b 1 0.1% 3340C>T R1070W 17b 1 0.1% 3408C>A Y1092X 17b 7 0.9% 3442G>T E1104X 17b 1 0.1% 3446T>G ** M1105R 17b 1 0.1% 3586G>C D1152H 18 1 0.1% 3601-17T>C + 1367delC int 18 + 9 1 0.1% 3616C>T R1162X 19 1 0.1% 2 0.2% 3659delC 19 2 0.2% 3832A>G I1234V 19 2 0.3% 3849+4A>G int 19 1 0.1% 3849+10kbC>T int 19 3 0.2% 3877G>A G1249R 20 1 0.1% 3884G>A S1251N 20 1 0.1% 3898insC 20 1 0.1% 3905insT 20 2 0.3% 3978G>A W1282X 20 3 0.4% 4005+1G>A int 20 6 0.8% 4016insT 21 1 0.1% 4041C>G N1303K 21 11 1.4% 5 0.4% 4136T>C L1335P 22 1 0.1% 1 0.4% 4279insA 23 1 0.1% Unidentified Unidentified - 3 0.4% 41 3.2% 11 4.0% Total 778 100.0% 1262 100.0% 278 100.0% * All nucleotide changes correspond to cDNA numbering. Login to comment

[hide] Molecular consequences of cystic fibrosis transmem... Gut. 2003 Aug;52(8):1159-64. Ahmed N, Corey M, Forstner G, Zielenski J, Tsui LC, Ellis L, Tullis E, Durie P
Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas.
Gut. 2003 Aug;52(8):1159-64., [PMID:12865275]

Abstract [show]
BACKGROUND AND AIMS: We tested the hypothesis that the actual or predicted consequences of mutations in the cystic fibrosis transmembrane regulator gene correlate with the pancreatic phenotype and with measures of quantitative exocrine pancreatic function. METHODS: We assessed 742 patients with cystic fibrosis for whom genotype and clinical data were available. At diagnosis, 610 were pancreatic insufficient, 110 were pancreatic sufficient, and 22 pancreatic sufficient patients progressed to pancreatic insufficiency after diagnosis. RESULTS: We identified mutations on both alleles in 633 patients (85.3%), on one allele in 95 (12.8%), and on neither allele in 14 (1.9%). Seventy six different mutations were identified. The most common mutation was DeltaF508 (71.3%) followed by G551D (2.9%), G542X (2.3%), 621+1G-->T (1.2%), and W1282X (1.2%). Patients were categorized into five classes according to the predicted functional consequences of each mutation. Over 95% of patients with severe class I, II, and III mutations were pancreatic insufficient or progressed to pancreatic insufficiency. In contrast, patients with mild class IV and V mutations were consistently pancreatic sufficient. In all but four cases each genotype correlated exclusively with the pancreatic phenotype. Quantitative data of acinar and ductular secretion were available in 93 patients. Patients with mutations belonging to classes I, II, and III had greatly reduced acinar and ductular function compared with those with class IV or V mutations. CONCLUSION: The predicted or known functional consequences of specific mutant alleles correlate with the severity of pancreatic disease in cystic fibrosis.

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308 The exception, a patient with the class IV mutation I1234V, developed PI at the age of 25 years, after symptoms of chronic pancreatitis lasting 10 years. Login to comment
309 Table 2 Genotype classification according to the functional consequences of CFTR gene mutations Pancreatic status Class I Class II Class III Class IV Class V PS F1 , 875+1G→C(2) F, F (1) F, G551D (1) F, R117H (11) F,3849+10kbC→T (5) F, G85E2 (1) F, R347H (3) F,3272-26A→G (4) F, S1251N (2) F,A445E (3) F, D614G (1) F,P574H (2) F, R347P (1) F,3120G>A (1) R117H,R117H (1) F, 5T (8) F, L1335P (1) F,2789+5G→A (1) F,P67L (1) F,R347P/R347H (1) F,V232D(2) R334W, R334W(1) PS→PI F,3659delC (1) F,F (15) F,G551D (1) F, I1234V (1) F,2184insA (1) F,R560T (1) PI F, G542X (27) F,F (365) F, G551D (28) F, 621+1G→T (13) F, R560T (7) F,R553X (7) F, N1303K (9) F, R1162X (6) F,L1077P (2) F, 3659delC (5) F, I48T (1) F, 1717-1G→A (5) F,A559T (1) F, W1282X (5) F, G85E2 (2) F, 711+1G→T (5) G551D,G551D(1) F,2184delA(4) F,H199R (1) W1282X,W1282X (4) F,I1072T(1) F,Y1092X (3) F,S549 (R75Q) (1) F,556delA (3) F, Q493X (3) F,4016InsT (3) F, 3120+1G→A (2) F, G551D/R553X (2) F,Q814X(2) F,1154insTC (2) F,441delA (1) F, 4326delTC (1) F,Q552X(1) F,3007delG (1) F,2184insA (1) F, 4010del4 (1) F,3905insT (1) F,1078delT(1) F,E1104X (1) F,3876delA (1) F,4374+1G→T (1) F,E585X (1) F, E60X (1) CFTR, cystic fibrosis transmembrane regulator; PI, pancreatic insufficiency; PS, pancreatic sufficiency. Login to comment

[hide] Microbiological identification in cystic fibrosis ... J Trop Pediatr. 2004 Aug;50(4):229-33. Wahab AA, Janahi IA, Marafia MM, El-Shafie S
Microbiological identification in cystic fibrosis patients with CFTR I1234V mutation.
J Trop Pediatr. 2004 Aug;50(4):229-33., [PMID:15357563]

Abstract [show]
Recurrent and chronic bacterial pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Over 6 months, 72 sputa or oropharyngeal samples were examined from 36 Arab Bedouin CF patients attending Hamad General Hospital, Doha, Qatar. More than 100 pathogens were isolated, mostly Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa. Unusual pathogens included Stenotrophomonas maltophilia, Acaligenes xylosoxidans and Mycobacterium abscessus. It is concluded that microbiological biodiversity in the lower airways of CF patients continues to be underestimated and that CF patients harbouring mucoid strains of P. aeruginosa are at a higher risk of acquiring more unusual organisms and probably have a worse prognosis.

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6 All the patients were homozygous for the I1234V mutation of CFTR gene in exon 19. Login to comment
7 They were seen every 10-12 weeks in the paediatric outpatient CF clinic and additionally in acute situations. At each visit, or hospital admission the height and weight Journal of Tropical Pediatrics, Vol. 50, No. 4  Oxford University Press 2004; all rights reserved 229 Microbiological Identification in Cystic Fibrosis Patients with CFTR I1234V Mutation by A. Abdul Wahab,a I. A. Janahi,a M. M. Marafia,a and S. El-Shafieb Departments of a Pediatrics and b Microbiology, Hamad Medical Corporation, Doha, Qatar Summary Recurrent and chronic bacterial pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Login to comment
47 A. ABDUL WAHAB ET AL. 230 Journal of Tropical Pediatrics Vol. 50, No. 4 TABLE 1 Data concerning isolation of organisms from patient with CF mutation I1234V (n = 36) Total H. influenza 32 S. aureus 28 Pseudomonas (mucoid) 9 Pseudomonas (non-mucoid) 9 S. maltophilia 2 Candida species 9 A. baumanni 3 A. xylosoxidans 2 Streptococcus pyogenes 5 Streptococcus pneumoniae 2 Streptococcus agalactiae Gr B 1 Streptococcus Group C 1 Mycobacterium avium intracellulare 2 M. abscessus 2 Campylobacter 1 Proteus mirabilis 1 It was noted that those with pancreatic insufficiency had higher rates of persistent pulmonary infection and more frequent hospitalization for acute respiratory exacerbation. Login to comment
53 Discussion This study gives details of the microbiological spectrum of lower airway cultures in a large cohort of CF patients with a similar CFTR mutation I1234V. Login to comment
59 Data collected in a 1998 multicentre study of CF patients A. ABDUL WAHAB ET AL. Journal of Tropical Pediatrics Vol. 50, No. 4 231 TABLE 2 Data concerning isolation of organisms from patient with CF mutation I1234V (n = 36) in different age groups Age groups --------------------- < 9 years > 9 years Count (%) Count (%) Total H. influenza 9 (28.1) 23 (71.9) 32 S. aureus 11 (39.3) 17 (60.7) 28 Pseudomonas (mucoid) 1 (11.1) 8 (88.9) 9 Pseudomonas (non-mucoid) 2 (22.2) 7 (77.8) 9 S. maltophilia 2 (100). Login to comment

[hide] Mutation spectrum in Jewish cystic fibrosis patien... Am J Med Genet A. 2005 Jul 30;136(3):246-8. Quint A, Lerer I, Sagi M, Abeliovich D
Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening.
Am J Med Genet A. 2005 Jul 30;136(3):246-8., 2005-07-30 [PMID:15948195]

Abstract [show]
We have tested 144 unrelated Jewish patients suffering from the classical form of cystic fibrosis. The patients were screened for a panel of 12 mutations including the six Ashkenazi founder mutations (DeltaF508, W1282X, N1303K, G542X, 3849 + 10 kb C-->T, 1717-1G > A) and six mutations that were found in non-Ashkenazi Jewish patients (S549R (T-->G), G85E, 405 + 1G-->A, W1089X, Y1092, and D1152H). Patients of Georgian origin were tested also for the Q359K/T360K mutation. In addition, all the patients were tested for the IVS-8 variant (9T/7T/5T). Of all the cystic fibrosis (CF)-bearing chromosomes, 94% (264/281) were accounted for by one of the known mutations, and none of the patients had the 5T allele of the IVS-8 variant. Single strand conformation polymorphism (SSCP) analysis of the coding sequence of the CFTR gene followed by sequencing showed eight mutations on ten CF chromosomes, leaving seven chromosomes (2.5%) with unknown mutations. We identified three mutations in two or more CF chromosomes, 2571 + 1insT in Jews from Iraq, 3121-1G > A in patients from Kurdistan and I1234V in Yemenite Jewish patients. The other five mutations appeared on a single allele and are considered "private mutations." In this study we have identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews of North African origin and 75% in Jewish patients from Iraq. The significance of these findings to the population screening in Israel is discussed.

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6 We identified three mutations in two or more CF chromosomes, 2571 þ 1insT in Jews from Iraq, 3121-1G > A in patients from Kurdistan and I1234V in Yemenite Jewish patients. Login to comment
54 Both had the I1234V mutation while the second mutation was DF508 in one patient and W1282X in the other. Login to comment
55 We also identified the I1234V mutation in a patient with CBAVD and IVS8-5T variant on the second chromosome. Login to comment
57 The I1234V mutation was described in Arab patients from the Arabian peninsula [Claustres et al., 1992; Kambouris et al., 2000] and several homozygous patients from a Beduin tribe in Qatar were described with variable clinical manifestations TABLE I. 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
59 We found the mutation I1234V in 1 of 120 anonymous Yemenite Jews. Login to comment
69 We suggest that 15 mutations that were found on two or more CF chromosomes from unrelated patients (DF508, W1282X, N1303K, G542X, 3849 þ 10 kb C!T, 1717-1 G!A, S549R (T!G), G85E, 405 þ 1G!A, W1089X, Y1092X, 2751 þ 1insT, 3121-1G!A, Q359K/T360K, I1234V) be tested in the CF screening of all Jewish individuals regardless of their origin. Login to comment

[hide] Faecal elastase-1 concentration in cystic fibrosis... Acta Paediatr. 2006 Sep;95(9):1066-9. Abdel Rahman H, Abdul Wahab A, Abdel Rahman MO, Mostafa OA
Faecal elastase-1 concentration in cystic fibrosis patients with CFTR I1234V mutation.
Acta Paediatr. 2006 Sep;95(9):1066-9., [PMID:16938751]

Abstract [show]
AIM: To assess the exocrine pancreatic function among cystic fibrosis patients with cystic fibrosis trans-membrane conductance regulator (CFTR) I1234V mutation. METHODS: Cross-sectional study of 40 cystic fibrosis patients with homozygous CFTR I1234V mutation belonging to a large Arab kindred family and 25 healthy subjects as a control group over a period of 12 mo. Assessment of their exocrine pancreatic function was performed by measuring faecal elastase-1 (FE1) concentration with a commercial ELISA kit using polyclonal antibodies (BioServ Diagnostics) in CF patients compared to healthy subjects. The results were compared with those obtained from a second laboratory using another commercial ELISA (ScheBo; Biotech, Germany) that uses two monoclonal antibodies against different specific epitopes of human pancreatic elastase. RESULTS: All CF patients with CFTR I1234V mutation had normal levels of faecal elastase 1. No significant difference was found between the two methods for the CF groups or between the CF patients with and without pancreatic enzyme replacement. CONCLUSION: Cystic fibrosis with homozygous CFTR I1234V mutation is associated with pancreatic sufficiency. Assessment of exocrine function using polyclonal antibodies does not significantly differ from that using two monoclonal antibodies against different specific epitopes of human pancreatic elastase.

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0 Faecal elastase-1 concentration in cystic fibrosis patients with CFTR I1234V mutation H. ABDEL RAHMAN1 , A. ABDUL WAHAB1 , M. O. ABDEL RAHMAN2 & OSSAMA ABDEL RAHMAN MOSTAFA3 Departments of 1 Paediatrics and Biochemistry, 2 Hamad Medical Corporation, Doha, Qatar, and 3 Beni Suef Faculty of Medicine, Beni Suef, Egypt Abstract Aim: To assess the exocrine pancreatic function among cystic fibrosis patients with cystic fibrosis trans-membrane conductance regulator (CFTR) I1234V mutation. Login to comment
1 Methods: Cross-sectional study of 40 cystic fibrosis patients with homozygous CFTR I1234V mutation belonging to a large Arab kindred family and 25 healthy subjects as a control group over a period of 12 mo. Login to comment
4 Results: All CF patients with CFTR I1234V mutation had normal levels of faecal elastase 1. Login to comment
6 Conclusion: Cystic fibrosis with homozygous CFTR I1234V mutation is associated with pancreatic sufficiency. Login to comment
8 Key Words: Cystic fibrosis, CFTR mutation I1234V, faecal elastase, pancreatic function Introduction Cystic fibrosis (CF) is an inherited disorder, caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Login to comment
20 CFTR I1234V mutation is one of the common mutations among Arabs in the Gulf region, and yet the exocrine pancreatic function has not been studied objectively [10,11]. Login to comment
21 The purpose of our study was to assess exocrine pancreatic function among cystic fibrosis patients with CFTR I1234V mutation by measuring faecal pancreatic elastase-1 activity. Login to comment
25 E-mail: atiqa@qatar.net.qa/atiqaaw@yahoo.com/atiqa@hmc.org.qa Acta Pædiatrica, 2006; 95: 1066Á1069 Patients and methods Patients Forty CF patients with homozygous CFTR I1234V mutation were evaluated (22 males and 18 females belonging to a large Arab kindred family). Login to comment
56 A thorough review of the literature proved that there were no previous studies that objectively evaluated pancreatic status with CFTR I1234V mutation [10,11]. Login to comment
58 Moreover, the concentration of FE1 in healthy controls was not significantly different from that of CF patients, suggesting that CF patients with CFTR I1234V mutation have sufficient exocrine pancreatic function. Login to comment
63 Our results revealed normal FE1 among CF patients, including those patients older than 15 y, suggesting that these CF patients with CFTR I1234V mutation are unlikely to have mild pancreatic insufficiency. Login to comment
76 These patients had normal levels of faecal elastase, similar to those CF patients without pancreatic enzyme replacement, indicating that our CFTR I1234V mutation is a mild genotype mutation associated with pancreatic sufficiency. Login to comment
77 In summary, CFTR I1234V mutation is associated with pancreatic sufficiency. Login to comment
78 It is therefore recommended that pancreatic replacement therapy not be supplemented in cases of cystic fibrosis with CFTR I1234V mutation. Login to comment

[hide] The changing face of the exocrine pancreas in cyst... Eur J Gastroenterol Hepatol. 2008 Mar;20(3):164-8. Augarten A, Ben Tov A, Madgar I, Barak A, Akons H, Laufer J, Efrati O, Aviram M, Bentur L, Blau H, Paret G, Wilschanski M, Kerem BS, Yahav Y
The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype.
Eur J Gastroenterol Hepatol. 2008 Mar;20(3):164-8., [PMID:18301294]

Abstract [show]
OBJECTIVES: The aims of this study were to determine the current pancreatic status of the entire cystic fibrosis (CF) population of Israel, to analyze the clinical characteristics of the pancreatic sufficient (PS) patients, and to characterize the correlation between pancreatic status, pancreatitis, and CF genotype. METHODS: The Israeli CF database includes 505 patients. These patients were defined as being PS or insufficient according to their fecal pancreatic elastase level or by coefficient fat absorption findings. Mutations were categorized as severe (DeltaF508, W1282X, G542X, S549R, N1303K, Q359K/T360K, 405+1G, and 1717) or mild/variable (3849+10 kb, D1152H, G85E, I1234V, R334W, and 5T) based on disease severity in patients carrying these mutations. Age at diagnosis, presenting symptoms, sweat-chloride concentrations, occurrence of pancreatitis, presence of diabetes, and liver disease were recorded. RESULTS: One hundred and thirty-nine (27.5%) of the CF patients were PS. None carried two mutations associated with severe disease. Over one third (34%) had normal or borderline sweat tests; 20 of these 139 patients had pancreatitis (14.3%) but none of the 366 pancreatic insufficient patients had it. Four initially PS patients became pancreatic insufficient: conversion followed several events of pancreatitis in three of them. Nasal potential differences were all pathological in 35 tested PS patients. None had either diabetes or liver disease. CONCLUSIONS: A substantial number of CF patients are PS. All of them carry at least one mild mutation enabling production of a sufficient amount of normal mRNA to maintain exocrine pancreatic function. Pancreatitis occurs only in CF patients who are PS. These patients are at risk of progressing to pancreatic insufficiency.

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23 The mutations DF508, W1282X, G542X, S549R, Q359K/T360K, 405 + 1G, 1717, and N1303K were defined as severe and the mutations 3849 + 10 kb, D1152H, G85E, I1234V, R334W, and 5T were defined as mild/variable. Login to comment
46 of patients W1282X/3849 + 10 kb 15 W1282X/5T 15 DF508/5T 7 DF508/D1152H 6 DF508/3849 + 10 kb 5 W1282X/D1152H 5 W1282X/I1234V 2 3849 + 10 kb/405 + 1G- > A 2 R334W/R334W 2 5T/5T 2 D1152H/D1152H 1 D1152H/5T 1 D1152H/3849 + 10 kb 1 DF508/UKN 13 W1282X/UKN 11 5T/UKN 7 D1152H/UKN 3 1717/UNK 1 G85E/UKN 1 Q359K/T360K/UKN 1 S549R/UKN 1 3849 + 10 kb/UKN 1 UKN/UKN 36 CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane regulator. Login to comment
69 Table 3 The clinical characteristics of the PS patients who became PI Age at CF diagnosis Presenting symptom Age at first pancreatitis event Age at transition PS-PI Genetic profile Sweat Clmmol/l 19 years Pulmonary 19 yearsa 22 years W1282X/G85E 66 6 months Affected sibling 3 yearsa 14 years W1282X/I1234V 82 1 month Affected sibling (None) 12 years DF508/G85E 32 28 years Pancreatitis 28 yearsa 34 years D1152H/5T 30 CF, cystic fibrosis; PI, pancreatic insufficient; PS, pancreatic sufficient. Login to comment
72 The other mutations carried by the PS group (D1152H, G85E, I1234V, and R334W) were also found to cause variable clinical expressions [7-10]. Login to comment

[hide] Mutations that permit residual CFTR function delay... Respir Res. 2010 Oct 8;11:140. Green DM, McDougal KE, Blackman SM, Sosnay PR, Henderson LB, Naughton KM, Collaco JM, Cutting GR
Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients.
Respir Res. 2010 Oct 8;11:140., [PMID:20932301]

Abstract [show]
BACKGROUND: Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF. METHODS: Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories. RESULTS: Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile). CONCLUSIONS: Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.

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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

[hide] The D1152H cystic fibrosis mutation in prenatal ca... J Med Screen. 2011;18(4):169-72. Epub 2011 Dec 7. Peleg L, Karpati M, Bronstein S, Berkenstadt M, Frydman M, Yonath H, Pras E
The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis.
J Med Screen. 2011;18(4):169-72. Epub 2011 Dec 7., [PMID:22156145]

Abstract [show]
OBJECTIVE: To assess the frequency of the D1152H mutation in the CFTR gene in normal individuals, in cystic fibrosis (CF) patients and in the setting of prenatal diagnosis. SETTING: A database analysis of sequential screening results seen at the Sheba Medical Center, Israel, between 2001 and 2010. METHODS: We retrospectively analyzed the frequency of D1152H in a large cohort of healthy individuals who were screened as part of a routine prenatal care programme, in individuals referred due to CF-related symptoms and in the setting of prenatal diagnosis. RESULTS: We found one asymptomatic homozygous female and 195 D1152H carriers among 49,940 healthy individuals screened, establishing a carrier rate of 1:255 for this mutation. We detected D1152H in nine of 103 individuals referred due to CF-related symptoms. Four suffered from respiratory symptoms and five from congenital bilateral absence of the vas deferens (CBAVD). During this period D1152H was detected in three pregnancies, two of which were aborted. CONCLUSION: The increased frequency of D1152H in individuals referred due to CF-related symptoms compared with healthy individuals included in the CF carrier screening programme (P < 0.001) clearly indicates that it is a disease-causing mutation.

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180 of mutations Group of mutations 2001 Ashkenazi Jews 7 Group A Non-Ashkenazi Jews 11 Group A þ B Georgian Jews 12 Group A þ B þ T360K/Q359K 9.2004-7.2005 Yemenite Jews 12 Groups A þ B þ I1234V Iraqi Jews 12 Groups A þ B þY1092X 8.2005-12.2007 Iraqi Jews 14 Groups A þ B þY1092X þ 3121-1G-A 1.2008-2010 14 mutations for all 14 Groups A þ B þ C Georgian Jews 15 Groups A þ B þ C þ T360K/Q359K Arabic population 19 Groups A þ B þ C þ D Group A: G542X, W1282X, N1303K, F508del, 3849 þ 10KbC-T, 1717-1G-A, D1152H Group B: W1089X, G85E, 405 þ 1G-A, S549R(T-G) Group C: Y1092X, 3121-1G-A, I1234V Group D: 4010delTATT, S549I, 3120 þ 1Kbdel18.6Kb, 2183AA-G, R75X Between 2005-2008 the Iraqi population was screened for an additional mutation 2751 þ 1insT. Login to comment

[hide] The K+ channel opener 1-EBIO potentiates residual ... PLoS One. 2011;6(8):e24445. Epub 2011 Aug 31. Roth EK, Hirtz S, Duerr J, Wenning D, Eichler I, Seydewitz HH, Amaral MD, Mall MA
The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients.
PLoS One. 2011;6(8):e24445. Epub 2011 Aug 31., [PMID:21909392]

Abstract [show]
BACKGROUND: The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K(+) channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl(-) secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. METHODS: We studied the effects of 1-EBIO on CFTR-mediated Cl(-) secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl(-) secretion. RESULTS: Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl(-) secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl(-) secretion by 39.2+/-6.7% (P<0.001) via activation of basolateral Ca(2)(+)-activated and clotrimazole-sensitive KCNN4 K(+) channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl(-) secretion in tissues with residual CFTR function by 44.4+/-11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl(-) conductance. CONCLUSIONS: We conclude that 1-EBIO potentiates Cl(-)secretion in native CF tissues expressing CFTR mutants with residual Cl(-) channel function by activation of basolateral KCNN4 K(+) channels that increase the driving force for luminal Cl(-) exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF.

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46 CFabsent CFresidual CFTR genotype Number of individuals CFTR genotype Number of individuals F508del/F508del 10 F508del/Y161C 1 F508del/W57X 1 F508del/V232D 1 F508del/G85E 3 F508del/R334W 2 F508del/120del23 1 F508del/T338I 1 F508del/182delT 1 F508del/I1234V 1 F508del/G542X 1 F508del/3272-26 A.G 1 F508del/A561E 1 F508del/3849+10 kb C.T 1 F508del/Y1092X 1 F508del/4005 +5727 A.G 1 F508del/N1303K 1 F508del/G576A 1 F508del/1525-1 G.A 2 N1303K/R334W 1 F508del/Q39X 1 F1052V/M1137R 1 F508del/Q552X 1 1898+3 A.G/ 1898+3 A.G 1 G85E/G85E 1 R334W/3199del6 1 Q552X/R1162X 1 R334W/X 1 A561E/A561E 2 dele2,3/X 1 R764X/1717-1 G.A 1 R1158X/2183AA.G 1 R1158X/R560T 1 doi:10.1371/journal.pone.0024445.t001 luminal and basolateral surfaces of the epithelium were perfused continuously with a solution of the following composition (mmol/ L): NaCl 145, KH2PO4 0.4, K2HPO4 1.6, D-glucose 5, MgCl2 1, Ca-gluconate 1.3, pH 7.4, at 37uC. Login to comment

[hide] Cystic fibrosis: a new mutation in the Lebanese po... J Cyst Fibros. 2008 Sep;7(5):429-32. Epub 2008 May 2. Farra C, Medawar R, Mroueh S, Souaid M, Cabet F, Awwad J
Cystic fibrosis: a new mutation in the Lebanese population.
J Cyst Fibros. 2008 Sep;7(5):429-32. Epub 2008 May 2., [PMID:18455968]

Abstract [show]
BACKGROUND: Cystic fibrosis is the most common autosomal recessive disorder in Caucasians. Little has been reported on its occurrence in Arab and Lebanese populations where mutation distribution seems to differ from that of Europeans. We report on the occurrence of a frameshift mutation 4016insG in two Lebanese Muslim siblings, products of consanguineous parents. This mutation generates a stop codon instead of Arginine-1301 and has never been reported before. METHODS: Both probands manifested early onset of severe respiratory and pancreatic involvement. DNA analysis was performed by PCR and sequencing for exons 1, 4, 10, 11, 20, 21 of the CFTR gene. RESULTS: Both probands were found to be homozygous for the 4016insG. Their parents were both heterozygous for the same mutation. CONCLUSION: The frameshift mutation reported in this article is being described for the first time.

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46 Recently, a panel of 11 common mutations accounting overall for 70% of all Arab CF chromosomes have been reported : ΔF508del, 3120+1G"A, N1303K, W1282X, G115X, 711+1G"A, S549R, I1234V, 1548delG , H139L and 4010del4 [9]. Login to comment

[hide] High heterogeneity of CFTR mutations and unexpecte... J Cyst Fibros. 2004 Dec;3(4):265-72. des Georges M, Guittard C, Altieri JP, Templin C, Sarles J, Sarda P, Claustres M
High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France.
J Cyst Fibros. 2004 Dec;3(4):265-72., [PMID:15698946]

Abstract [show]
In this report, we present updated spectrum and frequency of mutations of the CFTR gene that are responsible for cystic fibrosis (CF) in Languedoc-Roussillon (L-R), the southwestern part of France. A total of 75 different mutations were identified by DGGE in 215 families, accounting for 97.6% of CF genes and generating 88 different mutational genotypes. The frequency of p.F508del was 60.23% in L-R versus 67.18% in the whole country and only five other mutations (p.G542X, p.N1303K, p.R334W, c.1717-1G>A, c.711+1G>T) had a frequency higher than 1%. The mutations were scattered over 20 exons or their border. This sample representing only 5.7% of French CF patients contributed to 24% of CFTR mutations reported in France. This is one of the highest molecular allelic heterogeneity reported so far in CF. We also present the result of a neonatal screening program based on a two-tiered approach "IRT/20 mutations/IRT" analysis on blood spots, implemented in France with the aim to improve survival and quality of life of patients diagnosed before clinical onset. This 18-month pilot project showed an unexpected low incidence of CF (1/8885) in South of France, with only six CF children detected among 43,489 neonates born in L-R, and 13 among 125,339 neonates born in Provence-Alpes-Cote-d'Azur (PACA).

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69 of chromosomes (frequency %) p.E1104X 17b 2 (0.47) p.R1158X 19 3 (0.70) p.R1162X 19 2 (0.47) c.3659delC 19 1 (0.23) c.3737delA 19 2 (0.47) p.I1234V 19 1 (0.23) c.3849+10kbCNT intron 19 4 (0.93) c.3850-1GNA intron 19 1 (0.23) p.G1244E 20 1 (0.23) p.W1282X 20 2 (0.47) p.N1303H 21 1 (0.23) p.N1303K 21 13 (3.02) p.Q1313X 21 1 (0.23) c.4382delA 24 1 (023) Mutations described for the first time by our laboratory appear in bold. Login to comment

[hide] CFTR Cl- channel function in native human colon co... Gastroenterology. 2004 Oct;127(4):1085-95. Hirtz S, Gonska T, Seydewitz HH, Thomas J, Greiner P, Kuehr J, Brandis M, Eichler I, Rocha H, Lopes AI, Barreto C, Ramalho A, Amaral MD, Kunzelmann K, Mall M
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.
Gastroenterology. 2004 Oct;127(4):1085-95., [PMID:15480987]

Abstract [show]
BACKGROUND & AIMS: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. METHODS: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. RESULTS: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. CONCLUSIONS: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.

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78 Relationship Between the CFTR Genotype and Cl- Channel Function in Native Rectal Epithelia CFTR genotype Number of individuals Sweat Cl-concentration (mmol/L)a cAMP-mediated response Carbachol-induced plateau response or maximal lumen-negative response Isc-cAMP (␮A/cm2) Cl- secretion (% of control) Isc-carbachol (␮A/cm2) Cl- secretion (% of control) Cl- secretion absent R1162X/Q552X 1 71 17.1 0 0.7 0 W1282X/3121-2AϾG 1 112 1.9 0 0.6 0 1898 ϩ 1G Ͼ T/1609delCA 2b 114, 118 25.4, 13.4 0, 0 0, 0.7 0, 0 ⌬F508/Q39X 2b 127, 129 2.6, 4.4 0, 0 1.7, 3.7 0, 0 ⌬F508/G542X 1 102 29.0 0 6.6 0 ⌬F508/R553X 3 112, 102, 109 13.1, 4.5, 23.8 0, 0, 0 1.5, 4.4, 1.0 0, 0, 0 ⌬F508/E585X 1 115 1.4 0 1.1 0 ⌬F508/Q637X 1 100 2.9 0 1.2 0 ⌬F508/Y1092X 1 119 0.0 0 -0.3 0 ⌬F508/120del23c 1 72 20.1 0 3.3 0 ⌬F508/182delT 1 116 10.8 0 5.2 0 ⌬F508/3905insT 2 88, 96 8.4, 5.6 0, 0 2.3, -1.1 0, 1 ⌬F508/V520F 1 68 1.2 0 1.7 0 ⌬F508/A561E 3 113, 146, 100 17.0, 17.0, 16.0 0, 0, 0 2.1, 1.5, 3.7 0, 0, 0 ⌬F508/R1066C 1 138 0.0 0 0.0 0 ⌬F508/N1303K 3 100, 117, 94 1.7, 4.1, 1.5 0, 0, 0 -0.6, 2.2, 0.8 0, 0, 0 A561E/A561E 2 101, 116 6.6, 2.0 0, 0 7.3, 3.3 0, 0 Residual Cl- secretiond G542X/I148N 1 75 -50.1 54 -22.2 12 1898 ϩ 3A Ͼ G/1898 ϩ 3A Ͼ G 1 82 -36.8 39 -12.9 7 ⌬F508/3272-26A Ͼ G 1 116 -17.8 19 -27.2 14 ⌬F508/S108F 1 118 -15.8 17 -12.3 7 ⌬F508/R117H 1 90 -35.9 38 -207.7 109 ⌬F508/Y161Cc 1 44 -35.1 37 -45.9 25 ⌬F508/P205S 1 80 -23.3 25 -10.4 5 ⌬F508/V232D 1 120 -16.9 18 -26.9 14 ⌬F508/R334W 1 92 -22.1 23 -21.1 11 ⌬F508/R334W 1 101 -24.5 26 -37.4 20 ⌬F508/T338I 1 73 -44.4 47 -79.4 42 ⌬F508/G576A 1 40 -16.9 18 -115.5 61 ⌬F508/I1234V 1 113 -13.6 15 -8.6 5 G576A/G85E 1 95 -26.1 28 -61.6 32 F1052V/M1137R 1 47 -36.7 39 -146.6 77 M1101K/M1101K 1 94 -11.1 12 -4.8 3 S1159F/S1159F 1 67 -47.9 51 -38.7 21 N1303K/R334W 1 91 -30.3 32 -47.7 25 NOTE. CFTR Cl- channel function was determined in rectal epithelia from Cl- secretory responses induced by IBMX/forskolin (Isc-cAMP) and after co-activation with carbachol (Isc-carbachol). Login to comment
101 Functional Classification and Protein Location of CFTR Mutations Mutation type Severe mutations (protein location) Mild mutations (protein location) Missense V520F, A561E (NBD1) G85E (MSD1, TM1) R1066C (MSD2, CL4) S108F, R117H (MSD1, EL1) N1303K (NBD2) I148N, Y161Ca (MSD1, CL1) P205S (MSD1, TM3) V232D (MSD1, TM4) R334W, T338I (MSD1, TM6) G576A (NBD1) I1234V (NBD2) F1052V, M1101K (MSD2, CL4) M1137R (MSD2, TM12) S1159F (pre-NBD2) Splice 1898 ϩ 1G Ͼ T (R domain) 1898 ϩ 3A Ͼ G (R domain) 3121-2A Ͼ G (MSD2, TM9) 3272-26A Ͼ G (MSD2, TM10) Single amino acid deletion ⌬F508 (NBD1) Nonsense Q39X (N-terminus) G542X, Q552X, R553X, E585X (NBD1) Q637X (R domain) Y1092X (MSD2, CL4) R1162X (pre-NBD2) W1282X (NBD2) Frameshift 120del23a 182delT (N-terminus) 1609delCA (NBD1) 3905insT (NBD2) NOTE. Severe mutation, Cl- secretion absent; mild mutation, residual cAMP-mediated Cl- secretion. Login to comment
125 According to our functional data, 3121-2AϾG, 1898ϩ1GϾT, and V520F constitute severe mutations, whereas 1898ϩ3AϾG, I148N, Y161C, V232D, T338I, I1234V, and S1159F confer residual CFTR Cl- channel function (Table 1). Login to comment

[hide] Spectrum of CFTR mutations in cystic fibrosis and ... Hum Mutat. 2000;16(2):143-56. Claustres M, Guittard C, Bozon D, Chevalier F, Verlingue C, Ferec C, Girodon E, Cazeneuve C, Bienvenu T, Lalau G, Dumur V, Feldmann D, Bieth E, Blayau M, Clavel C, Creveaux I, Malinge MC, Monnier N, Malzac P, Mittre H, Chomel JC, Bonnefont JP, Iron A, Chery M, Georges MD
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.
Hum Mutat. 2000;16(2):143-56., [PMID:10923036]

Abstract [show]
We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 19 laboratories in France. We have analyzed 7, 420 CF alleles, demonstrating a total of 310 different mutations including 24 not reported previously, accounting for 93.56% of CF genes. The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Only 11 mutations had relative frequencies >0. 4%, 140 mutations were found on a small number of CF alleles (from 29 to two), and 154 were unique. These data show a clear geographical and/or ethnic variation in the distribution of the most common CF mutations. This spectrum of CF mutations, the largest ever reported in one country, has generated 481 different genotypes. We also investigated a cohort of 800 French men with congenital bilateral absence of the vas deferens (CBAVD) and identified a total of 137 different CFTR mutations. Screening for the most common CF defects in addition to assessment for IVS8-5T allowed us to detect two mutations in 47.63% and one in 24.63% of CBAVD patients. In a subset of 327 CBAVD men who were more extensively investigated through the scanning of coding/flanking sequences, 516 of 654 (78. 90%) alleles were identified, with 15.90% and 70.95% of patients carrying one or two mutations, respectively, and only 13.15% without any detectable CFTR abnormality. The distribution of genotypes, classified according to the expected effect of their mutations on CFTR protein, clearly differed between both populations. CF patients had two severe mutations (87.77%) or one severe and one mild/variable mutation (11.33%), whereas CBAVD men had either a severe and a mild/variable (87.89%) or two mild/variable (11.57%) mutations.

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104 c 4016insT, G1244E, R1158X, 3120+1G>A, 1677delTA, I1234V, E831X, 5T, Q220X, E92K, G91R. Login to comment
140 Non-F508del Mutations Found as Homozygous in a Sample of 3,710 Patients With Cystic Fibrosis Mutation n 711+1G>T 8 G542X 7 N1303K 7 2183delAA>G 5 W1282X 4 G551D 3 3905insT 3 R334W 2 R347P 2 1078delT 2 1811+1.6kbA>G 2 2113delA 2 Y1092X 2 R1162X 2 306insA 1 E92K 1 G178R 1 L227R 1 1677delTA 1 1717-1G>A 1 1717-8G>A 1 R553X 1 S549R(T>G) 1 R560S 1 V562I 1 Y569D 1 2711delT 1 S945L 1 R1158X 1 I1234V 1 3849+10kbC>T 1 Q1313X 1 del25kb 1 E831X 1 I175V 1 G314V 1 L1077P 1 produce a small quantity of functional protein as a result of a variable proportion of normal CFTR mRNA transcripts in addition to the abnormal ones (class V); 3) they are located in sites known to generate less severe mutants (external loops, residues lining the pore); and/or 4) they have been observed in CF with pancreatic sufficiency, CBAVD, and/or CF-related attenuated phenotypes only. Login to comment

[hide] Novel and characteristic CFTR mutations in Saudi A... J Med Genet. 1997 Dec;34(12):996-9. el-Harith EA, Dork T, Stuhrmann M, Abu-Srair H, al-Shahri A, Keller KM, Lentze MJ, Schmidtke J
Novel and characteristic CFTR mutations in Saudi Arab children with severe cystic fibrosis.
J Med Genet. 1997 Dec;34(12):996-9., [PMID:9429141]

Abstract [show]
More than 600 different CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations have been identified so far that are considered to cause the fatal genetic disorder cystic fibrosis (CF). We have investigated 15 Arab children from 12 families, who were diagnosed as having CF, for mutations in the coding region and in the flanking intron sequences of the CFTR gene. Six different CFTR mutations were identified including two novel mutations, 1548delG in exon 10 and 406-2A-->G in intron 3. Prominent mutations were the splice mutation 3120 + 1G-->A (intron 16) followed by N1303K (exon 21) and 1548delG (exon 10). Most CF children were homozygotes who presented with a severe form of the disease including failure to thrive, recurrent chest infections, particularly with Pseudomonas aeruginosa, and frequent hospital admissions. Identification of the CFTR mutations facilitates molecular investigation of the disease and better understanding of its pathophysiology in Arab children, among whom CF is probably an underdiagnosed disease.

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23 Table 1 CFTR mutations in 12 Arab CFfamilies Nucleotide Allele Mutation change Locationi frequenicy Reference 3120+1G- A3120+1G-AIntron 16 3 (21%) 14 N1303K 4041C-G Exon 21 2 (14%) 12 1548delG 1548delG Exon 10 2 (14%) This study 406-2A--G 406-2A-G Intron 3 1 (7%) This study 2043delG 2043delG Exon 13 1 (7%) 13 I1234V 3832A- G Exon 19 1 (7%) 15 Unknown 4 (29%) Mutations identified in 12 Arab CF families are listed by decreasing frequency. Login to comment
39 1548delG, I1234V, and 406-2A--G. Login to comment
54 In the second family, a single CF child carried 1548delG with _0 iN If 4a El-Harith et al Table 2 CFTR mutation genotypes and clinical phenotypes of 12 Arab children with cysticfibrosis Age Sweat Pseudonionas Patient chloride Meconiuni Pancreatic aeruginosa No Genotype Sex c ad (nniol/ll) ileus status colonisation 4075 406-2A--G/406-2A--G F 1.5 ab 90 Yes PI No CF30 1548deIG/N1303K F 0.3 ab 180 No PI No CF32 1548deIG/N1303K M 7.0 0.8 110 No PI No CF40 1548delG/unknown M 1.0 0.5 70 No PI Yes CF01 2043delG/2043delG F 0.3' ab 65 Yes PI Yes CF10 3120+1G-A/3120+1G-A M 2.7 0.7 129 No PI Yes CF16 3120+1G-.A/3120+1G-A F 3.0 ab 121 Yes PI Yes CF46 3120+1G-A/3120+1G--A M 4.6 0.3 75 No PI Yes CF49 3120+1G-A/3120+1G-'A M 1.0 0.1 100 No PI Yes CF25 11234V/11234V F 5.5 0.5 62 No PI Yes CF28 I1234V/11234V F 1.0 0.5 65 No PS No CF19 N1303K/N1303K F 2.6 2.0 60 No PI Yes Clinical features of 12 Arab CF children with identified CFTR mutation genotypes. Login to comment
66 The I1234V mutation'5 was seen in the homozygous state in two sisters (aged 5 months and 5 years) who presented with failure to thrive and recurrent diarrhoea. Login to comment
67 The I1234V mutation'5 was seen in the homozygous state in two sisters (aged 5 months and 5 years) who presented with failure to thrive and recurrent diarrhoea. Login to comment

[hide] Sensitivity of single-strand conformation polymorp... Hum Mol Genet. 1994 May;3(5):801-7. Ravnik-Glavac M, Glavac D, Dean M
Sensitivity of single-strand conformation polymorphism and heteroduplex method for mutation detection in the cystic fibrosis gene.
Hum Mol Genet. 1994 May;3(5):801-7., [PMID:7521710]

Abstract [show]
The gene responsible for cystic fibrosis (CF) contains 27 coding exons and more than 300 independent mutations have been identified. An efficient and optimized strategy is required to identify additional mutations and/or to screen patient samples for the presence of known mutations. We have tested several different conditions for performing single-stranded conformation polymorphism (SSCP) analysis in order to determine the efficiency of the method and to identify the optimum conditions for mutation detection. Each exon and corresponding exon boundaries were amplified. A panel of 134 known CF mutations were used to test the efficiency of detection of mutations. The SSCP conditions were varied by altering the percentage and cross-linking of the acrylamide, employing MDE (an acrylamide substitute), and by adding sucrose and glycerol. The presence of heteroduplexes could be detected on most gels and in some cases contributed to the ability to distinguish certain mutations. Each analysis condition detected 75-98% of the mutations, and all of the mutations could be detected by at least one condition. Therefore, an optimized SSCP analysis can be used to efficiently screen for mutations in a large gene.

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46 cd,e,f.gformatjon of heteroduplexes in DNA samples containing the following mutations increases the sensitivity to 100%: 1833delT; E827X; Q1291R; G551D, R553X, R553Q; I1234V, 3850-3T-G; respectively. Login to comment
121 1078delT (35), L327R (Ravnik-Glavac a al., unpublished), R334W (36), D36K (31), R347L (26), R347P (14), A349V (26), R352Q (30), 1221delCT (34); Exon 8: W401X (31), 1342-1G-C (25); Exon 9: G458V (37), 1525 -1G-A (38); Exon 10: S492F (34), Q493X (39), 1609delCA (40,17), deltaI507 (39,41), deltaF5O8 (3), 1717-1G-A (39,42); Exon 11: G542X (39), S549N, G551D, R553X (43), R553Q (44), A559T (43), R560K (Fine et al., pers. comm.), R560T (39); Exon 12: Y563N (39), 1833delT (Schwartz et al., pers. comm.), P574H (39), 1898 + 1G-C (31), 1898+3A-G (Ferrari et al., pers. comm.); Exon 13: G628R(G-C) (31), Q685X (Firec et al., pers. comm.), K716X (26), L719X (Dork etal., pers. comm.), 2522insC (15), 2556insAT (45), E827X (34); Exon 14a: E831X (Ffrec et al., pers. comm.), R851X (29), 2721delll (31), C866Y (Audrezet et al., pers. comm.); Exon 14b: 2789+5G-A (Highsmith et al., pers. comm.); Exon 15: 2907denT (21), 2991del32 (Dark and TQmmler, pers. comm.), G970R (31); Exon 16: S977P, 3100insA (D6rk et al., pers. comm.); Exon 17a: I1005R (Dork and TQmmler, pers. comm.), 3272-1G-A (46); Exon 17b: H1054D (F6rec et al., pers. comm.), G1061R (Fdrec et al., pers. comm.), 332Oins5, R1066H, A1067T (34), R1066L (Fe"rec etal., pers. comm.), R1070Q (46), E1104X (Zielenski el al., pers. comm.), 3359delCT (46), L1077P (Bozon « a/., pers. comm.), H1085R (46), Y1092X (Bozon etal., pers. comm.), W1098R, M1101K (Zielenski et al., pers. comm.); Exon 18: D1152H (Highsmith et al., pers. comm.); Exon 19:R1162X (36), 3659delC (39), 3662delA (25), 3667del4 (Chillon et al., pers. comm.), 3737ddA (35), 3821ddT (15), I1234V (35), S1235R (31), Q1238X (26), 3849G-A (25), 385O-3T-G (38); Exon20:3860ins31 (Chillon etal., pers. comm.), S1255X (47), 3898insC (26), 3905insT (Malik et al., pers. comm.), D127ON (48), W1282X (49), Q1291R (Dork et al., pers. comm.), Exon 21: N1303H (35), N13O3K (50), W1316X (43); Exon 22: 11328L/4116delA (Dork and TQmmler, pers. comm.), E1371X (25); Exon 23: 4374+ 1G-T (38); Exon 24: 4382delA (Claustres et al., pers. comm.). Login to comment

[hide] Analysis of the CFTR gene confirms the high geneti... Hum Genet. 1994 Apr;93(4):447-51. Chillon M, Casals T, Gimenez J, Ramos MD, Palacio A, Morral N, Estivill X, Nunes V
Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes.
Hum Genet. 1994 Apr;93(4):447-51., [PMID:7513293]

Abstract [show]
We have analysed 972 unrelated Spanish cystic fibrosis patients for 70 known mutations. Analysis was performed on exons 1, 2, 3, 4, 5, 6a, 6b, 7, 10, 11, 12, 13, 14a, 14b, 15, 16, 17b, 18, 19, 20 and 21 of the cystic fibrosis transmembrane regulator gene using single strand conformation polymorphism analysis and denaturing gradient gel electrophoresis. The major mutation delta F508 accounts for 50.6% of CF chromosomes, whereas another 42 mutations account for 27.6% of CF chromosomes, with 21.8% of Spanish CF chromosomes remaining uncharacterized. At present, we have identified 36 mutations that have frequency of less than 1% and that are spread over 15 different exons. This indicates that, in the Spanish population, with the exception of delta F508 (50.6%) and G542X (8%), the mutations are not concentrated in a few exons of the gene nor are there any predominating mutations. This high degree of genetic heterogeneity is mainly a result of the different ethnic groups that have populated Spain and of the maintenance of separated population sets (Basques, Arab-Andalusian, Mediterranean, Canarian and Gallician). The high proportion of CF chromosomes still unidentified (21.8%) together with association analysis with intragenic markers suggest that at least 100 different mutations causing CF are present in our population.

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31 At present, we have not detected any Spanish CF chromosomes bearing any of the following mutations: 394delTA, Y122X, 556delA, 852de122, R347P, $492F, 1677delTA, V520F, Q552X, R553X, L559S, R560K, R560T, Y563N, P564H, 2043delG, 3320ins5, R1066H, A1067T, H1085R, 3732delA, 3737delA, I1234V, S1255P, 3898insC, Q1291H or 4005+ 1G---~A. Login to comment

[hide] CFTR gene mutations and asthma in the Norwegian En... Respir Med. 2006 Dec;100(12):2121-8. Epub 2006 May 5. Munthe-Kaas MC, Lodrup Carlsen KC, Carlsen KH, Skinningsrud B, Haland G, Devulapalli CS, Pettersen M, Eiklid K
CFTR gene mutations and asthma in the Norwegian Environment and Childhood Asthma study.
Respir Med. 2006 Dec;100(12):2121-8. Epub 2006 May 5., [PMID:16678395]

Abstract [show]
BACKGROUND: Several candidate genes have been implicated in the etiology of asthma, including the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations in the CFTR gene result in derangements of mucociliary clearance. Homozygotes for CFTR mutations develop cystic fibrosis (CF), a disorder characterized mainly by lung and pancreas disease. OBJECTIVE: To investigate whether there was an increased frequency of CFTR mutations in asthma patients. METHODS: Seven hundred and three subjects aged 10-11 years from the environment and childhood asthma (ECA) study were included in the present study. Possible associations between asthma, reduced lung function, bronchial hyperresponsiveness (BHR), and increased or decreased nitrogen oxide (NO) levels (based on structural parental interview, spirometry, PD20 methacholine challenge test and exhaled NO measurements), and the five most common CFTR mutations in Norway (DeltaF508, R117H, R117C, 4005+2T-->C, 394delTT), the modulating polymorphisms IVS8(TG)mTn and the IVS8-5T were investigated. RESULTS: No association were found between asthma, reduced lung function, BHR or exhaled NO levels and CF heterozygosity. However, the IVS8(TG)11T7 haplotype was associated with normal lung function. CONCLUSIONS: Our results do not support the hypothesis that CFTR mutations or polymorphisms play a role in the pathogenesis of asthma in children. However, the distribution of Tn(TG)m haplotypes differed between individuals with reduced lung function and individuals with normal lung function.

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25 CFTR mutation Alleles (%) F508del 184 (62.2) R117C 12 (4.1) R117H 12 394delTT 11 (3.8) 4005+2T-C 11 G551D 6 (2.0) 3659delC 5 (1.7) E60X 4 (1.4) V232D 4 1525-2A-G 3 (1.0) N1303K 3 G542X 2 (0.7) E279X 2 R75X 2 S912X 2 E116X 1 (0.3) L295Q 1 R347L 1 Q493X 1 I506L 1 I507del 1 R553X 1 G576A 1 621-1G-T 1 2183AA-G 1 S945L 1 R1162X 1 I1234V 1 3849+10 kbC-T 1 W1282X 1 Unknown 18 (6.5) Total alleles 296 (100%) Mutations detected with OLA31 m kit-74%. Login to comment

[hide] Defining the disease liability of variants in the ... Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25., [PMID:23974870]

Abstract [show]
Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of l0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.

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197 For example, it is possible that one or more of the indeterminate variants cause dysfunction of CFTR in a manner distinct from the functional assessments used in this study, as has been shown for two missense changes that also affect RNA splicing (p.Gly576Ala58 and p.Ile1234Val; A.S.R. and M.D.A., unpublished data). Login to comment

[hide] Genotypic diversity of Pseudomonas aeruginosa in c... Eur J Clin Microbiol Infect Dis. 2014 Feb;33(2):265-71. doi: 10.1007/s10096-013-1954-1. Epub 2013 Sep 1. Abdul Wahab A, Taj-Aldeen SJ, Hagen F, Diophode S, Saadoon A, Meis JF, Klaassen CH
Genotypic diversity of Pseudomonas aeruginosa in cystic fibrosis siblings in Qatar using AFLP fingerprinting.
Eur J Clin Microbiol Infect Dis. 2014 Feb;33(2):265-71. doi: 10.1007/s10096-013-1954-1. Epub 2013 Sep 1., [PMID:23996049]

Abstract [show]
Pseudomonas aeruginosa is one of the primary pathogens in patients with cystic fibrosis (CF) and a major cause of morbidity and mortality. Reports of the spread of epidemic or transmissible strains of P. aeruginosa within and across CF centers raised the possibility of clonal spread among siblings with CF. This work reports the genotypic relatedness of P. aeruginosa in CF patients with the CFTR I1234V mutation, and to determine whether the genotypes are identical among CF siblings and among different families with the same CFTR mutation. Sixty-six P. aeruginosa isolates were obtained from sputa/deep-pharyngeal swabs from 27 CF patients belonging to 17 families. Genotypic relatedness was assessed using amplified fragment-length polymorphism (AFLP) fingerprinting. Twenty-three distinct genotypes of P. aeruginosa were identified. Eleven families each had one distinct genotype. In the other 6 families more than one genotype was observed; 3 families each showed two genotypes, 2 families each had three genotypes and 1 family had four genotypes of P. aeruginosa. In several cases, siblings with CF from the same family harbored the same strain of P. aeruginosa, which were different from the genotypes in other families. On the other hand, there was an overlap in P. aeruginosa between closely related families. Some patients show persistent colonization with the same genotype of P. aeruginosa over the longitudinal period. The presence of the same genotypes in siblings of the same family and closely related families suggests cross-transmission of P. aeruginosa or acquisition from common environmental exposure.

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3 This work reports the genotypic relatedness of P. aeruginosa in CF patients with the CFTR I1234V mutation, and to determine whether the genotypes are identical among CF siblings and among different families with the same CFTR mutation. Login to comment
22 The CFTR I1234V mutation is one of the common mutations among Arabs in the Gulf region belonging to a large kindred Arab tribe [13, 14]. Login to comment
23 The prevalence of P. aeruginosa in lower respiratory cultures of CF patients with CFTR I1234V mutation was 60.9 % [15]. Login to comment
27 Materials and methods Patients and sampling Between March 2010 and June 2011, sputum samples or deep pharyngeal swabs were prospectively collected and cultured from CF patients with the CFTR I1234V mutation attending the CF clinic at Hamad Medical Corporation, Doha, Qatar. Login to comment
42 Twelve families (F1-12 constitute 22 CF patients with CFTR I1234V mutation (denoted as "A" in Table 1) belong to a single large Arab kindred tribe with positive P. aeruginosa culture. Login to comment

[hide] Genetic, cell biological, and clinical interrogati... Genet Med. 2014 Aug;16(8):625-32. doi: 10.1038/gim.2014.4. Epub 2014 Feb 20. Molinski SV, Gonska T, Huan LJ, Baskin B, Janahi IA, Ray PN, Bear CE
Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention.
Genet Med. 2014 Aug;16(8):625-32. doi: 10.1038/gim.2014.4. Epub 2014 Feb 20., [PMID:24556927]

Abstract [show]
PURPOSE: The purpose of this study was to determine the molecular consequences of the variant c.3700 A>G in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a variant that has been predicted to cause a missense mutation in the CFTR protein (p.Ile1234Val). METHODS: Clinical assays of CFTR function were performed, and genomic DNA from patients homozygous for c.3700 A>G and their family members was sequenced. Total RNA was extracted from epithelial cells of the patients, transcribed into complementary DNA, and sequenced. CFTR complementary DNA clones containing the missense mutation p.Ile1234Val or a truncated exon 19 (p.Ile1234_Arg1239del) were constructed and heterologously expressed to test CFTR protein synthesis and processing. RESULTS: In vivo functional measurements revealed that the individuals homozygous for the variant c.3700 A>G exhibited defective CFTR function. We show that this mutation in exon 19 activates a cryptic donor splice site 18 bp upstream of the original donor splice site, resulting in deletion of six amino acids (r.3700_3717del; p.Ile1234_Arg1239del). This deletion, similar to p.Phe508del, causes a primary defect in folding and processing. Importantly, Lumacaftor (VX-809), currently in clinical trial for cystic fibrosis patients with the major cystic fibrosis-causing mutation, p.Phe508del, partially ameliorated the processing defect caused by p.Ile1234_Arg1239del. CONCLUSION: These studies highlight the need to verify molecular and clinical consequences of CFTR variants to define possible therapeutic strategies.

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5 Submitted 18 October 2013; accepted 6 January 2014; advance online publication 20 February 2014. doi:10.1038/gim.2014.4 Purpose: The purpose of this study was to determine the molecular consequences of the variant c.3700 A>G in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a variant that has been predicted to cause a missense mutation in the CFTR protein (p.Ile1234Val). Login to comment
8 CFTR complementary DNA clones containing the missense mutation p.Ile1234Val or a truncated exon 19 (p.Ile1234_ Arg1239del) were constructed and heterologously expressed to test CFTR protein synthesis and processing. Login to comment
15 Correspondence: Christine E. Bear (bear@sickkids.ca) Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention Steven V. Molinski, MSc1,2 , Tanja Gonska, MD3,4 , Ling Jun Huan, BSc1 , Berivan Baskin, PhD5 , Ibrahim A. Janahi, MD6 , Peter N. Ray, PhD7,8 and Christine E. Bear, PhD1,2,9 A recent, large-scale study showed that individuals in North America and Europe bearing the rare variant c.3700 A>G, predicted to cause the missense mutation p.Ile1234Val or alternativesplicing,exhibitedvariableCFdiseaseseverity.6 Thisvariant, although rare in North America (present in only 15 patients, http://cftr2.org), is relatively common in the Middle East. Login to comment
17 who.int/genomics/publications) report p.Ile1234Val as the second most common CF-causing mutation in the Middle East (12.3% occurrence in patients from Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, and United Arab Emirates), with the exception of two countries, Bahrain and Israel, in which the occurrence is less than 3.8 and 0.06%, respectively. Login to comment
19 Furthermore, the c.3700 A>G (p.Ile1234Val) mutation is specific to Middle Eastern individuals originating from Bedouin tribes, and although diagnostic tests are sensitive enough to identify this mutation at an early age, currently there is no effective treatment for patients with this CF-causing genotype.23 Interestingly, Sosnay et al.6 recently showed that there were no functional consequences of introducing the missense mutation (p.Ile1234Val) in CFTR complementary DNA (cDNA) with respect to CFTR protein synthesis, processing, and/or function. Login to comment
37 Generation of mutant CFTR constructs p.Ile1234Val-CFTR was generated in human wild-type (WT)- CFTR cDNA (pcDNA3.1) by Norclone Biotech Laboratories (London, ON, Canada). Login to comment
41 Studies of CFTR protein processing and function Human embryonic kidney cells were transiently transfected with WT-CFTR or p.Ile1234Val-CFTR using PolyFect Transfection Reagent, according to the manufacturer`s protocol (Qiagen, Venlo, the Netherlands). Login to comment
45 Human embryonic kidney cells expressing WT-CFTR or p.Ile1234Val-CFTR and BHK cells expressing WT-CFTR, p.Phe508del-CFTR, or p.Ile1234_Arg1239del-CFTR were grown at 37 &#b0;C for 24ߙ h and subsequently lysed in modified radioimmunoprecipitation assay buffer (50 mmol/l Tris-HCl, 150 mmol/l NaCl, 1 mmol/l ethylenediaminetetraacetic acid (pH 7.4), 0.2% (v/v) sodium dodecyl sulfate, and 0.1% (v/v) Triton X-100) containing a protease inhibitor cocktail (Roche, Indianapolis, IN) for 10ߙ min, and the soluble fractions were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis on 6% gels. Login to comment
53 To test function, human embryonic kidney cells overexpressing WT-CFTR or p.Ile1234Val-CFTR were grown in 12-well plates, and on formation of a monolayer, the cells were incubated overnight with 10 mmol/l of the halide-sensitive fluorophore 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ; Invitrogen Molecular Probes, Carlsbad, CA), at 37 &#b0;C and 5% CO2 . Login to comment
68 RESULTS Siblings in a Qatari family homozygous for the CFTR variant c.3700 A>G exhibit clinical features of CF and lack of CFTR function in in vivo measurements A 27-year-old man and his 15-year-old sister, both from Qatar and homozygous for the mutation c.3700 A>G (p.Ile1234Val), presentedforfurtherCFdiagnosticevaluation.Theman,patient 1, was diagnosed at 4 months of age and had experienced recurrent lung infection over the years. Login to comment
86 Determining the consequences of p.Ile1234Val on CFTR folding, processing, and function The CFTR variant c.3700 A>G has been predicted to create a missense mutation (p.Ile1234Val). Login to comment
95 Figure 1ߒ Qatari siblings with cystic fibrosis transmembrane conductance regulator (CFTR) variant c.3700 A>G (predicted to cause the CFTR missense mutation: p.Ile1234Val) exhibit loss of CFTR function in nasal potential difference (NPD) and sweat secretion assays. Login to comment
114 This clinical phenotype is incompatible with the prediction that this variant caused the missense mutation, p.Ile1234Val. Login to comment
115 Cell-based studies of the predicted missense mutation introduced into CFTR cDNA showed that the predicted missense mutation, p.Ile1234Val, caused no apparent defects in protein folding, processing, or function.Thesefindingspromptedadetailedanalysisoftheentire CFTRgeneandCFTRmRNAobtainedfromthenasalepithelium of a homozygous patient with the detection of aberrant splicing. Login to comment
120 The effect of p.Ile1234_Arg1239del on protein folding and processing is consistent with bioinformatics predictions Examination of homology models and bioinformatics analyses predict that p.Ile1234_Arg1239del will cause significant Figure 2ߒ In vitro characterization of p.Ile1234Val missense mutation introduced into cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA and expressed in heterologous expression system. Login to comment
121 (a) Immunoblots show the processing of wild-type (WT)-CFTR and p.Ile1234Val-CFTR in human embryonic kidney (HEK) cells after 24ߙh at 37 &#b0;C. WT-CFTR and p.Ile1234Val-CFTR were expressed as both the Golgi-modified, complex glycosylated (mature) band C form (broad 170-kDa band) as well as the endoplasmic reticulum-modified, core glycosylated (immature), band B form (sharp 150-kDa band). Login to comment
122 Maturation (expressed as percentage of band C/ (band B + band C)) of WT-CFTR and p.Ile1234Val-CFTR was quantified for three independent trials, and there was no significant difference between the two (P > 0.05). Login to comment
123 (b) Fluorescence-based anion flux assay in HEK cells show WT-CFTR and p.Ile1234Val-CFTR function after stimulation using a cAMP agonist (gray bar, forskolin, 10 bc;mol/l) or vehicle (dimethyl sulfoxide) alone (empty bar). Login to comment
124 Flux responses in the first 4ߙmin after cAMP stimulation (reported as an initial rate of change in relative fluorescence units (RFU)) for WT-CFTR and p.Ile1234Val-CFTR were quantified for three independent trials (four technical replicates each trial), and there was no significant difference between the two (P > 0.05). Login to comment

[hide] Defining a mutational panel and predicting the pre... Sultan Qaboos Univ Med J. 2014 Aug;14(3):e323-9. Epub 2014 Jul 24. Fass UW, Al-Salmani M, Bendahhou S, Shivalingam G, Norrish C, Hebal K, Clark F, Heming T, Al-Khusaiby S
Defining a mutational panel and predicting the prevalence of cystic fibrosis in oman.
Sultan Qaboos Univ Med J. 2014 Aug;14(3):e323-9. Epub 2014 Jul 24., [PMID:25097766]

Abstract [show]
OBJECTIVES: Cystic fibrosis transmembrane conductance regulator (CFTR) mutations form distinct mutational panels in different populations and subgroups. The frequency of cystic fibrosis (CF) mutations and prevalence are unknown in Oman. This study aimed to elucidate the mutational panel and prevalence of CF for the North Al Batinah (NAB) region in Oman and to estimate the national prevalence of CF based on the carrier screening of unrelated volunteers. METHODS: The study included retrospective and prospective analyses of CF cases in the NAB region for 1998-2012. Genetic analysis of disease-causing mutations was conducted by screening of the entire coding sequence and exon-intron borders. The obtained mutational panel was used for the carrier screening of 408 alleles of unrelated and unaffected Omani individuals. RESULTS: S549R and F508del were the major mutations, accounting for 89% of mutations in the patient population. Two private mutations, c.1733-1734delTA and c.1175T>G, were identified in the patient cohort. Two carriers, one for F508del and another for S549R, were identified by screening of the volunteer cohort, resulting in a predicted prevalence for Oman of 1 in 8,264. The estimated carrier frequency of CF in Oman was 1 in 94. The carrier frequency in the NAB region was 3.9 times higher. CONCLUSION: The mutational panel for the NAB region and the high proportion of S549R mutations emphasises the need for specific screening for CF in Oman. The different distribution of allele frequencies suggests a spatial clustering of CF in the NAB region.

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128 For instance, the most common Saudi mutations 1548delG and I1234V are reported mainly in the central region of the country whereas the mutation 3120+1G࢐A appears to be more predominant in the east.18 Furthermore, the mutation I1234V has been described in 17 families of the same kabilah in Qatar.33 The estimated carrier frequency for CF in Oman of 1/94 appears lower than the reported carrier frequency for the UAE of 1/64.11 However, the context of mutational clusters with increased CF allele frequencies in subpopulations might be an explanation for this difference. Login to comment

[hide] Improving newborn screening for cystic fibrosis us... Genet Med. 2015 Feb 12. doi: 10.1038/gim.2014.209. Baker MW, Atkins AE, Cordovado SK, Hendrix M, Earley MC, Farrell PM
Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study.
Genet Med. 2015 Feb 12. doi: 10.1038/gim.2014.209., [PMID:25674778]

Abstract [show]
Purpose:Many regions have implemented newborn screening (NBS) for cystic fibrosis (CF) using a limited panel of cystic fibrosis transmembrane regulator (CFTR) mutations after immunoreactive trypsinogen (IRT) analysis. We sought to assess the feasibility of further improving the screening using next-generation sequencing (NGS) technology.Methods:An NGS assay was used to detect 162 CFTR mutations/variants characterized by the CFTR2 project. We used 67 dried blood spots (DBSs) containing 48 distinct CFTR mutations to validate the assay. NGS assay was retrospectively performed on 165 CF screen-positive samples with one CFTR mutation.Results:The NGS assay was successfully performed using DNA isolated from DBSs, and it correctly detected all CFTR mutations in the validation. Among 165 screen-positive infants with one CFTR mutation, no additional disease-causing mutation was identified in 151 samples consistent with normal sweat tests. Five infants had a CF-causing mutation that was not included in this panel, and nine with two CF-causing mutations were identified.Conclusion:The NGS assay was 100% concordant with traditional methods. Retrospective analysis results indicate an IRT/NGS screening algorithm would enable high sensitivity, better specificity and positive predictive value (PPV). This study lays the foundation for prospective studies and for introducing NGS in NBS laboratories.Genet Med advance online publication 12 February 2015Genetics in Medicine (2015); doi:10.1038/gim.2014.209.

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31 Both methods used 5 &#b5;l of isolated DNA for the NGS assay. NGS assay for detection of CFTR mutations/variants CFTR mutations are described using both the international nomenclature of the Human Genome Variation Society Mutations that have varying consequences c.3454G>C (D1152H) c.3154T>G (F1052V) c.3208C>T (R1070W) c.2930C>T (S977F) - c.3808G>A (D1270N) c.3205G>A (G1069R) c.350G>A (R117H) PolyTG/ polyT - c.1736A>G (D579G) c.3209G>A (R1070Q) c.220C>T (R74W) - - Mutations still under evaluation c.2657ߙ+ߙ2_2657ߙ+ߙ3insA (2789ߙ+ߙ2insA) c.680T>G (L227R) c.1705T>G (Y569D) - - c.1841A>G (D614G) c.1673T>C (L558S) - - - c.3700A>G (I1234V) c. Login to comment

[hide] Profile of cystic fibrosis in a single referral ce... J Adv Res. 2014 Sep;5(5):563-8. doi: 10.1016/j.jare.2013.07.005. Epub 2013 Jul 15. El-Falaki MM, Shahin WA, El-Basha NR, Ali AA, Mehaney DA, El-Attar MM
Profile of cystic fibrosis in a single referral center in Egypt.
J Adv Res. 2014 Sep;5(5):563-8. doi: 10.1016/j.jare.2013.07.005. Epub 2013 Jul 15., [PMID:25685524]

Abstract [show]
It was generally believed that Cystic fibrosis (CF) is rare among Arabs; however, the few studies available from Egypt and other Arabic countries suggested the presence of many undiagnosed patients. The aim of the present study was to determine the frequency of CF patients out of the referred cases in a single referral hospital in Egypt. A total of 100 patients clinically suspected of having CF were recruited from the CF clinic of the Allergy and Pulmonology Unit, Children's Hospital, Cairo University, Egypt, throughout a 2 year period. Sweat chloride testing was done for all patients using the Wescor macroduct system for collection of sweat. Quantitative analysis for chloride was then done by the thiocyanate colorimetric method. Patients positive for sweat chloride (60 mmol/L) were tested for the DeltaF508 mutation using primer specific PCR for cystic fibrosis transmembrane conductance regulator (CFTR) gene. Thirty-six patients (36%) had a positive sweat chloride test. The main clinical presentations in patients were chronic cough in 32 (88.9%), failure to thrive in 27 (75%), steatorrhea in 24 (66.7%), and hepatobiliary involvement in 5 (13.9%). Positive consanguinity was reported in 50% of CF patients. Thirty-two patients were screened for DeltaF508 mutation. Positive DeltaF508 mutation was detected in 22 (68.8%) patients, 8 (25%) were homozygous, 14 (43.8%) were heterozygous, and 10 (31.3%) tested were negative. CF was diagnosed in more than third of patients suspected of having the disease on clinical grounds. This high frequency of CF among referred patients indicates that a high index of suspicion and an increasing availability of diagnostic tests lead to the identification of a higher number of affected individuals.

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130 In some cases, these more frequent mutations may be specific for a subset of the people in the Middle East defined by a common ethnic or religious background, e.g., the 1548delG mutation in Saudi Arabia [18,26], Bedouin tribes in the case of I1234V [27], the S549R (T > G) mutation in Bedouins from the United Arab Emirates and Oman [21], and the 548A > T mutation in Bahrain [28]. Login to comment

[hide] Comparative ex vivo, in vitro and in silico analys... J Cyst Fibros. 2015 Feb 27. pii: S1569-1993(15)00039-9. doi: 10.1016/j.jcf.2015.02.002. Ramalho AS, Clarke LA, Sousa M, Felicio V, Barreto C, Lopes C, Amaral MD
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations.
J Cyst Fibros. 2015 Feb 27. pii: S1569-1993(15)00039-9. doi: 10.1016/j.jcf.2015.02.002., [PMID:25735457]

Abstract [show]
The Cystic Fibrosis p.Ile1234Val missense mutation actually creates a new dual splicing site possibly used either as a new acceptor or donor. Here, we aimed to test the accuracy of in silico predictions by comparing them with in vitro and ex vivo functional analyses of this mutation for an accurate CF diagnosis/prognosis. To this end, we applied a new in vitro strategy using a CFTR mini-gene which includes the complete CFTR coding sequence plus intron 22 (short version) which allows the assessment of alternatively spliced mRNA levels as well as the properties of the resulting abnormal CFTR protein regarding processing, intracellular localization and function. Our data demonstrate that p.Ile1234Val leads to usage of the alternative splicing donor (but not acceptor) resulting in alternative CFTR transcripts lacking 18nts of exon 22 which produce a truncated CFTR protein with residual Cl- channel function. These results recapitulate data from native tissues of a CF patient. In conclusion, the existing in silico prediction models have limited application and ex vivo functional assessment of mutation effects should be made. Alternatively the in vitro strategy adopted here can be applied to assess the disease liability of mutations for an accurate CF diagnosis/prognosis.

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0 Original Article Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations Anabela S. Ramalho a,1 , Luka A. Clarke a , Marisa Sousa a , Ver&#f3;nica Felicio a , Celeste Barreto b , Carlos Lopes b , Margarida D. Amaral a,Ìe; a University of Lisboa, Faculty of Sciences, BioISI - Biosystems and Integrative Sciences Institute, Lisboa, Portugal b Hospital de Santa Maria, Lisboa, Portugal Received 9 October 2014; revised 9 January 2015; accepted 4 February 2015 Abstract The Cystic Fibrosis p.Ile1234Val missense mutation actually creates a new dual splicing site possibly used either as a new acceptor or donor. Login to comment
3 Our data demonstrate that p.Ile1234Val leads to usage of the alternative splicing donor (but not acceptor) resulting in alternative CFTR transcripts lacking 18 nts of exon 22 which produce a truncated CFTR protein with residual Cl-channel function. Login to comment
33 Herein, we have compared in silico prediction models with in vitro and ex vivo analyses of the CFTR mutation p.Ile1234Val or c.3700A N G (legacy name I1234V) in exon 22 [5-23] to assess the value of these approaches in assessing the consequences of alternative splicing mutations. Login to comment
35 Next, we assessed the RNA level in native tissues from a CF patient with the F508del/p.Ile1234Val genotype and our data evidenced the occurrence of alternative CFTR transcripts, corresponding to usage of the cryptic splice donor that is preferentially used vs the normal one. Login to comment
36 Finally, to elucidate how p.Ile1234Val affects splicing and to functionally characterize the CFTR protein resulting from the alternatively spliced transcript, we performed in vitro studies, using a mini-gene. Login to comment
37 Our data demonstrate that p.Ile1234Val does in fact affect splicing, resulting in the same alternative transcripts and generation of a truncated CFTR protein which is only residually processed and exhibiting reduced Cl-channel function. Login to comment
38 We conclude that the major defect associated with p.Ile1234Val is alternative splicing, but this was not adequately predicted by existing in silico prediction models. Login to comment
42 Patient, genotype nomenclature, nasal brushing and rectal biopsies RNA was collected from nasal and colon epithelial cells of a CF patient compound heterozygous for the [p.Ile1234Val (c.3700A N G)] + [p.Phe508del (c.1521_1523delCTT)] CFTR mutations. Login to comment
49 Transcript analyses The impact of p.Ile1234Val (c.3700A N G) mutation on pre-mRNA splicing was determined by RT-PCR in the region of exons 19-23 using the primers I1R and I1L (see Supplementary Table S1) as described [27]. Login to comment
52 To distinguish between transcripts resulting from both alleles an RT-PCR was done in the exon 22-23 region using the primers F2R(ex22) and I1L(ex23) (see Supplementary Table S1), as before [27] followed by hydrolysis with the restriction enzyme DdeI (New England BioLabs, Ipswich, USA) to distinguish between putative full length transcripts resulting from p.Phe508del and p.Ile1234Val alleles. Login to comment
53 Indeed, only transcripts resulting from the p.Ile1234Val allele (full length or alternatively spliced) possess the DdeI restriction site (C|TNAG) which is absent in p.Phe508del transcripts. Login to comment
54 Thus, the p.Ile1234Val transcripts will be hydrolysed into two fragments of: a) 164 nts and 75 nts (alternatively spliced transcripts, 239 bp); or b) 182 bp and 75 bp (normally spliced, full length transcripts, 257 bp) whereas from the p.Phe508del transcripts (257 nts) will not be hydrolysed by DdeI (see Supplementary Fig. S1). Login to comment
55 Quantitative real time PCR was performed essentially as described [28] using primers designed using Primer3 software (http://frodo.wi.mit.edu/) and specific for the full length (5'-CAGTAAGTCCTGGCCAGAGG-3') and alternatively spliced (5'-CATTTCCTTCTCAGTGGGCCT-3') products of the p.Ile1234Val allele (common reverse primer: 5'-GCTTTCC TCCACTGTTGCAAA-3'). Login to comment
59 In silico analysis of splicing consensus values and ESE prediction The normal and mutated sequences containing the exon 22 and IVS21 and IVS22 boarding regions (~100 nt each) were submitted to six independent splicing signal prediction open source programmes: Spliceview2 [29]; NNSPLICE3 [30], Human Splicing Finder4 [31]; NetGene2 World Wide Web Server5 [32]; Alternative Splice Site Predictor (ASSP) 6 [33]; and Spliceport7 [34], in order to determine the potential of usage for the new acceptor and donor created by the p.Ile1234Val (c.3700A N G) mutation. Login to comment
67 Site-directed mutagenesis was also used to introduce all mutations analysed here into the CFTR-IVS22art mini-gene or pNUT p.Ile1234Val-CFTR cDNA (see primers in Table S3). Login to comment
69 Stable CFTR-expressing BHK cells Baby hamster kidney (BHK) cells, grown in DMEM F12, with 5% FBS, 1% of PenStrep were transfected with the two pNUT-CFTR-IVS22art mini-gene constructs: wt and the p.Ile1234Val (c.3700A N G) mutant and also all CFTR minigene variants analysed as well as with the p.Ile1234Val- CFTRcDNA pNUT, to produce novel BHK cell lines as before [36]. Login to comment
93 Clinical data from the CF patient A female CF patient with the genotype p.Phe508del (c.1521_1523delCTT)/p.Ile1234Val (c.3700A N G) was the index case for this study. Login to comment
99 Processing and functional analysis of p.Ile1234Val CFTR mutant Given that the p.Ile1234Val (c.3700A N G) mutation was described [5] as a missense mutation, we first determined how this mutation affected protein processing and function. Login to comment
100 To this end, we produced a BHK stable cell line expressing the p.Ile1234Val-cDNA-CFTR mutant from which we analysed CFTR protein by Western blot (WB). Login to comment
101 Results (Fig. 1A) clearly show that the p.Ile1234Val cDNA-CFTR mutant is fully processed to its mature, fully-glycosylated form (band C), just like wt-cDNA-CFTR. Login to comment
102 To assess p.Ile1234Val-cDNA-CFTR Cl-channel activity, cells expressing this CFTR mutant were analysed by the iodide efflux technique (Fig. 1B) and data showed that again p.Ile1234Val-cDNA-CFTR presented Cl-channel function similar to wt-CFTR. Login to comment
113 Patient Age at diagnosis 5 Age (years) 25 Sex F Genotype [p.Phe508del] + [p.Ile1234Val] Sweat test (mEq/L)a 115 FVC % predicted 81% FEV1% predicted 69% Bacteria Sa, Pa Pancreatic status PS Nasal polyposis No FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; Pa; Pseudomonas aeruginosa. Login to comment
120 Processing and functional analysis of the p.Ile1234Val-CFTR mutant protein. Login to comment
121 A) BHK cells stably expressing wt, F508del (legacy name) and I1234V (legacy name) CFTR cDNA constructs (without introns) were analysed by WB using the 596 Ab specific to the epitope from aa 1204-1211 in the NBD2 domain of CFTR. Login to comment
123 Lane 1 - wt-CFTR, lane 2 - F508del-CFTR and lane 3 - BHK I1234V-cDNA CFTR. Login to comment
124 B) Results from functional assessment of I1234V-cDNA CFTR by the iodide efflux technique using Forskolin and Genistein as CFTR agonists. Login to comment
127 Analysis of the p.Ile1234Val mutation that corresponds to the 3700A N G alteration at the CFTR nucleotide sequence. Login to comment
130 From top to bottom: i) full-length transcripts with the p.Ile1234Val missense mutation will be obtained if wt splice sites are used instead of the cryptic ones; ii) if the cryptic donor is used instead of the normal IVS22 donor, an aberrant transcript lacking the last 18 nts of exon 22 will be produced; iii) if the cryptic acceptor is used instead of the normal IVS21 acceptor, an alternative transcript lacking the first 231 nts of exon 22 will be produced. Login to comment
136 3.4. Effect of CFTR p.Ile1234Val mutation at the mRNA level of a CF patient with [p.Phe508del] + [p.Ile1234Val] genotype In order to determine whether the splice sites created by the c.3700A N G mutation are used in vivo, CFTR transcripts from native tissues (nasal cells and colonic tissue) of the index CF patient were analysed by RT-PCR in the region of the mutation, i.e., ex19-ex23. Login to comment
144 To distinguish the transcripts resulting from each allele (p.Phe508del and p.Ile1234Val), we next performed RT-PCR in the ex22-ex23 region (see Materials and methods and Fig. S1B and C) followed by hydrolysed with the restriction enzyme DdeI. Login to comment
145 The enzyme has a recognition site in transcripts resulting from the p.Ile1234Val allele but not in F508del transcripts. Login to comment
146 The putative I1234V normal spliced (full-length 257 bp) would originate fragments of 182 bp and 75 bp; and the alternative transcripts (239 bp) would generate fragments of 164 bp and 75 bp. Login to comment
151 Relative quantitative transcript analysis by real-time PCR analysis (Table 3) indicates that the levels of transcripts in patients' cells are present in a ratio of between 32:68 and 48:52 (F508del(full): I1234V(altspliced)), based on data using primer pairs specific for the I1234V splice variant and the F508del mutation, respectively. Login to comment
152 These data suggest that two CFTR transcripts are present: the F508del transcript and the alternatively spliced transcript derived from the p.Ile1234Val allele. Login to comment
153 With the F508del specific primer the amounts of both transcripts are similar, but with the primers specific for the I1234V splice variant we seem to obtain more of the splice I1234V derived transcripts. Login to comment
154 However this may be explained by the higher efficiency of PCR amplification for fragments with a smaller length as the case of the I1234V alternative spliced fragment (less 18 nts). Login to comment
155 In the cellular models we could observe 100% of full-length transcripts for the cells expressing the IVS22 mini-gene and almost 100% of alternative splice transcripts for the I1234V IVS22 mini-gene. Login to comment
180 A) RT-PCR analysis of CFTR transcripts extracted from nasal brushing cells (NB) and colonic tissues from rectal biopsies (RB) from index CF patient (with the [p.Ile1234Val] + [p.Phe508del] genotype) and carriers using I1L (exon 23) and I1R (exon 19) primer. Login to comment
185 The enzyme has a recognition site in transcripts resulting from the p.Ile1234Val allele but not in F508del transcripts. Login to comment
186 The alternative transcripts from the p.Ile1234Val allele (239 nts fragment) will be hydrolysed to two fragments of 164 nts and 75 nts. Login to comment
187 In case full-length transcripts from the p.Ile1234Val allele are produced (257 nts), they will be hydrolysed by DdeI enzyme into two fragments of 182 nts and 75 nts. Login to comment
189 Lane 1 - DNA ladder - hyperladder V from Bioline, lane 2 - Products resulting from hydrolysis with DdeI restriction enzyme of the PCR products shown in lane 3, Lane 3 - RT-PCR products of transcripts extracted from nasal of the [p.Ile1234Val] + [p.Phe508del] patient with F2R and I1L primers. Login to comment
190 Table 3 Relative abundance of CFTR transcripts quantified by real-time PCR in a patient with the F508del/I1234V genotype. Login to comment
191 Relative transcript abundance (of 100%) Sample Full length Alternatively spliced F508del/I1234V (NB) - I1234V primer set 32.1% (=non altern. Login to comment
192 spliced) 67.9% F508del/I1234V (NB) - F508del primer set 47.6% 52.4% (=non F508del) IVS22 (BHK) 100% 0% IVS22 + I1234V (BHK) 2.4% 97.6% wt/wt (NB) 100% 0% F508del/F508del (NB)ߤ 100% 0% 7 revert the splicing defect caused by the 3700A N G mutation. Login to comment
197 RNA from BHK cells stably expressing the IVS22art-CFTR mini-gene (wt, mutant (p.Ile1234Val or 3700A N G) and mutant plus "fish revertant" (3704G N A)) was analysed by RT-PCR in the region of ex22 to ex23 (primers F2R and I1L). Login to comment
200 Importantly, data also show that the mutant IVS22art-CFTR mini-gene containing c.3700A N G (p.Ile1234Val) resulted in alternative splicing, yielding only one PCR fragment of smaller size that of wt-IVS22art (Fig. 4A, lanes 3 and 2, respectively). Login to comment
202 This mini-gene was thus able to mimic the in vivo splicing alteration produced by the c.3700A N G (p.Ile1234Val) mutation. Login to comment
208 Characterization of the p.Ile1234Val (c.3700A N G) using the IVS22art CFTR mini-gene. Login to comment
224 This protein is indeed significantly different from the one resulting from the p.Ile1234Val cDNA simply as a missense mutation (Fig. 1B, lane 3). Login to comment
225 The CFTR protein resulting from the "fish revertant" (c.3704G N A) which reverts the splicing of IVS22, is also correctly processed (Fig. 4B, lane 3), despite the fact that it has two missense mutations (p.Ile1234Val-c.3700A N G and p.Ser1235Asn-c.3704G N A). Login to comment
232 In contrast, the p.Ile1234Val missense protein has normal function when compared to wt-CFTR. Login to comment
242 In summary, the p.Ile1234Val (c.3700A N G) mutation alters CFTR splicing producing alternative transcripts lacking 18 nts, which are then translated into a protein lacking 6 aa that is only partially processed as most does not traffic to the PM, where it has reduced function as Cl-channel. Login to comment
266 We focussed on the c.3700A N G mutation, for which the cDNA based expression models would lead to the classification of the I1234V protein as non-CF causing, since this variant, if solely considered as the cDNA isoleucine to valine amino acid change, is normally processed and functional, as we also show here (Fig. 1). Login to comment
269 In contrast, using our mini-gene strategy that allows the in vitro analysis of the consequences of CFTR mutations both at the mRNA and protein levels, we demonstrate that the p.Ile1234Val/c.3700A N G mutation is in fact a splicing mutation which results in the production of CFTR transcripts lacking 18 nts of exon 22 leading to the production of a truncated protein lacking 6 amino acids at the N-terminal of the CFTR NBD2 domain (Fig. 3, Table 3). Login to comment
297 For these mutations we performed an analysis with the NNS software and found that 3 of these sites were recognized as splice sites, but only 2 (the GU created by the I175V and the GU created by I1234V) had higher scores than the normal splice site (see Table S14). Login to comment

[hide] A Genotypic-Oriented View of CFTR Genetics Highlig... Mol Med. 2015 Apr 21;21:257-75. doi: 10.2119/molmed.2014.00229. Lucarelli M, Bruno SM, Pierandrei S, Ferraguti G, Stamato A, Narzi F, Amato A, Cimino G, Bertasi S, Quattrucci S, Strom R
A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis.
Mol Med. 2015 Apr 21;21:257-75. doi: 10.2119/molmed.2014.00229., [PMID:25910067]

Abstract [show]
Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype-phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype-phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype-phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway.

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390 L1077P c.3230T>C CF-PI CF-causing p.Leu1077Pro Y1092X(C>A) c.3276C>A CF-PI CF-causing p.Tyr1092* M1137V c.3409A>G CFTR-RD nd p.Met1137Val D1152H c.3454G>C CF-PI,CF-PS,CFTR-RD varying clinical consequence p.Asp1152His R1162X c.3484C>T CF-PI CF-causing p.Arg1162* D1168G c.3503A>G CFTR-RD nd p.Asp1168Gly 3667ins4 c.3535_3536insTCAA CF-PI CF-causing p.Thr1179IlefsX17 S1206X c.3617C>A uncertain: CF-PI and/or CF-PS nd p.Ser1206* I1234V c.3700A>G CF-PI,CF-PS CF-causing p.Ile1234Val S1235R c.3705T>G CFTR-RD non CF-causing p.Ser1235Arg 3849+10kbC>T c.3717+12191C>T CF-PI,CF-PS CF-causing V1240G c.3719T>G CFTR-RD nd p.Val1240Gly G1244R c.3730G>A uncertain: CF-PI and/or CF-PS nd p.Gly1244Arg G1244E c.3731G>A CF-PI,CF-PS CF-causing p.Gly1244Glu G1247R(G>C) c.3739G>C CF-PS nd p.Gly1247Arg W1282X c.3846G>A CF-PI CF-causing p.Trp1282* Q1291R c.3872A>G CF-PI,CF-PS,CFTR-RD nd p.Gln1291Arg 4016insT c.3884_3885insT CF-PI CF-causing p.Ser1297PhefsX5 4040delA c.3908delA CF-PI nd p.Asn1303ThrfsX25 N1303K c.3909C>G CF-PI CF-causing p.Asn1303Lys ex22-24del c.3964-3890_4443+3143del9454ins5 CF-PI nd ex22,23del c.3964-78_4242+577del1532 CF-PI CF-causing 4168delCTAAGCC c.4036_4042del CF-PI nd p.Leu1346MetfsX6 G1349D c.4046G>A CF-PI CF-causing p.Gly1349Asp H1375P c.4124A>C uncertain: CF-PI and/or CF-PS nd p.His1375Pro S1455X c.4364C>G CF-PS,CFTR-RD nd p.Ser1455* Q1476X c.4426C>T CFTR-RD nd p.Gln1476* nd,Not determined.According to the three rules described (see Materials and Methods),each mutated allele was classified according to its clinical outcome.It was impossible to univocally assign 16 of the 125 different mutated alleles to one or more macrocategories.A comparison with the CFTR2 project (11) (http://www.cftr2.org) is shown.The alleles are ordered according to their nucleotidic position. Login to comment

[hide] The improvement of the best practice guidelines fo... Eur J Hum Genet. 2015 May 27. doi: 10.1038/ejhg.2015.99. Girardet A, Viart V, Plaza S, Daina G, De Rycke M, Des Georges M, Fiorentino F, Harton G, Ishmukhametova A, Navarro J, Raynal C, Renwick P, Saguet F, Schwarz M, SenGupta S, Tzetis M, Roux AF, Claustres M
The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.
Eur J Hum Genet. 2015 May 27. doi: 10.1038/ejhg.2015.99., [PMID:26014425]

Abstract [show]
Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized here, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented.European Journal of Human Genetics advance online publication, 27 May 2015; doi:10.1038/ejhg.2015.99.

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87 [Gln359Lys; Thr360Lys] L558S c.1673 T4C p.Leu558Ser Y569D c.1705 T4G p.Tyr569Asp D579G c.1736 A4G p.Asp579Gly D614G c.1841 A4G p.Asp614Gly S977F c.2930C4T p.Ser977Phe F1052V c.3154 T4G p.Phe1052Val G1069R c.3205G4A p.Gly1069Arg R1070Q c.3209G4A p.Arg1070Gln D1152H c.3454G4C p.Asp1152His I1234V c.3700 A4G p.Ile1234Val 5T c.1210 - 12[5] Examples of common not CF-causing variantsc R31C c.91C4T p.Arg31Cys R74W c.220C4T p.Arg74Trp R75Q c.224G4A p.Arg75Gln I148T c.443 T4C p.Ile148Thr M470V c.1408 A4G p.Met470Val G576A c.1727G4C p.Gly576Ala R668C c.2002C4T p.Arg668Cys V754M c.2260G4A p.Val754Met L997F c.2991G4C p.Leu997Phe I1027T c.3080 T4C p.Ile1027Thr R1070W c.3208C4T p.Arg1070Trp R1162L c.3485G4T p.Arg1162Leu Table 1 (Continued) HGVS nomenclature Legacy name cDNA nucleotide name Protein name S1235R c.3705 T4G p.Ser1235Arg D1270N c.3808G4A p.Asp1270Asn 7T c.1210-12[7] Abbreviation: HGVS, Human Genome Variation Society. Login to comment