ABCMdb

PMID: 8956039

Hughes DJ, Hill AJ, Macek M Jr, Redmond AO, Nevin NC, Graham CA
Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes.
Hum Mutat. 1996;8(4):340-7., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Val562Leu Fifteen of these mutations had not previouslybeen found in Northern Ireland, and two are novel, MlI(G>T) and V562L. Login to comment 6 ABCC7 p.Gly551Asp ABCC7 p.Arg117His The three major CF mutations in Northern Ireland are AF508, G551D, and R117H with respective frequencies of 68.O%, 5.19/0, and 4.1%. Login to comment 45 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg560Thr Prior to the DGGE study a variety of methods (see Tables 1 and 2) were used to screen for CFTR mutations, including single mutation assaysfor AF508, AI507, G55lD, G542X, R553X, R117H, R560T, 621+lG>T, and 3849+10kbC>T. Login to comment 46 ABCC7 p.Asn1303Lys ABCC7 p.Arg297Gln ABCC7 p.Glu60* Mutations R297Q, 557delT, and 3849G>A, first identified in Northern Irish CF patients, were identified by PCR assays and direct sequencing (Graham et al., 1991, 1992;Cutting et al., 1992), whereas E60X, 3659delC, and N1303K were found by automated fluorescent sequencing. Login to comment 53 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Arg560Thr ABCC7 p.Pro67Leu ABCC7 p.Val562Leu ABCC7 p.Arg297Gln ABCC7 p.Tyr563Asn ABCC7 p.Glu60* ABCC7 p.Tyr917Cys 35%) PAGE (278) Kerem et al.. 1989AF508 G551D R117H R560T G542X 621+1G>T A1507 E60X 3659delC R553X 3120G>A 1l54insTC 2789+5G>A N1303K MlI(G>T) QW P67L 557delT 711+3A>G L206W R297Q V520F V562L Y563N Y917C R1162X 3849G>A 3849 +10kbC>T 3850-1GBA W1282X 280 21 17 12 9 9 7 3 2 1 68.0 5.1 4.1 2.9 2.2 2.2 1.7 0.7 0.5 0.24 17-32-13 (38;27%j 17-31-13(24,17%) 16-07-17 16-30-13 plus14 rare haplotypes (29) 16-07-17 23-33-13 (4) 22-31-13 (2) 21-31-13 17-07-17 (5) 16-31-13 16-35-13 17-58-13 17-35-13 16-07-17 17-07-17 23-29-13 (1) 23-31-13 (1) 16-07-17 16-31-13 16-07-17 15-29-13 16-33-13 16-07-17 17-07-17 16-07-17 16-07-17 16-30-13 16-32-17 17-31-13 16-31-14 16-46-13 16-30-14 17-07-17 DGGE(2) ' RD ASO's (11) DGGE(6) RD AR (8) DGGE (1) RD PAGE (5) DGGE (2) SEQ SEQ (2) DGGE (1) RD DGGE DGGE DGGE SEQ DGGE DGGE DGGE SEQ DGGE DGGE SEQ DGGE DGGE DGGE DGGE DGGE SEQ RD DGGE DGGE Cutting et al.. 1990 Dean et al.. 1990 Kerem et al., 1990 Kerem et al.. 1990 Zielenski et al., 1991 Kerem et al.. 1990 Malone et al., CFGAC Kerem et al., 1990 Cutting et al., 1990 Zielenski et al., CFGAC lannuzzi et al., 1991 Highsmith et al., 1990 Osborne et al., 1991 this study Savov et al., 1994 Hamosh et al., CFGAC Graham et al., 1992 Petreska et al., CFGAC Claustres et al., 1993 Graham et al., 1991 Jones et al.. 1992 this study Kerem et al.. 1990 Edkins & Creegan, CFGAC Gasparini et al., 1991 Cutting et al.. 1992 Highsmith et al., 1994 Audriizet et al., 1993 Vidaud et al., 1990 "Numbers in parentheses after the microsatellite haplotypes refer to the number of alleles haplotyped when not all of the available chromosomeswere typed. Login to comment 66 ABCC7 p.Val562Leu V562L. Login to comment 70 ABCC7 p.Arg75Gln CFTR PolymorphismsIdentified in Northern Irish CF Population Variation 125G>C 129 G>C R75Q 1898+152T>A 2694 T or G 4374+13 A or G 4521 G or A also identified 3601-99 additional T (sequencecorrection) Location 5'UT 5'UT Exon 3 Intron 12 Exon 14a lntron 23 Exon 24 Intron 18 Frequency (%) 0.24 3.4 1.2 25 27 19 100 0.5 Identification by DGGE DGGE DGGE SEQ SEQ SEQ DGGE SEQ Reference Cuttinget al., 1992 Zielenski et al., 1991b Zielenski et al.. 1991a Chilldn et al.. CFGAC Zielenski et al., 1991a Costeset al., CFGAC Gasparini et al., 1991a this study ~ ~ TABLE3. Login to comment 71 ABCC7 p.Gly27* All Mutationsand Polvmorphisms(control and new) Identified by DGGE in This Studv 1 2 3 4 5 6a 6b 7 8 9 10 11 12 13partl 13part2 13part3 13part4 14a 14b 15 16 17a 17bpartl 17bpart2 18 19 20 21 22 23 24 _ _ _ _ _ ~ ~ ~ DGGE Denaturant Run time (exon) Mutation" (range of %) Voltage (hr) 125G>C (p),129G>C (p),M11 (G>T), Q2X, 182delT 40-80 150 4 G27X. Login to comment 72 ABCC7 p.Arg75Gln ABCC7 p.Pro67Leu ABCC7 p.Arg75* ABCC7 p.Glu60* 241delAT 40-70 40 16 E60X 394delTT, R75X R75Q (p),P67L. Login to comment 73 ABCC7 p.Arg117His ABCC7 p.Gly85Glu ABCC7 p.Leu88Ser G85E, L88S R117H, 621+1G>T, 435insA. Login to comment 74 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Leu206Trp ABCC7 p.His199Tyr ABCC7 p.Trp401* ABCC7 p.Arg297Gln 441delA, 557delT 711+1G>T, 711+3A>G H199Y, L206W 977insA R297Q 1078delT,R334W, 1154insTC, R347P W401X l46linsAGAT 1525- 1G>A, A1507, AI5071AF508. Login to comment 75 ABCC7 p.Gln493* ABCC7 p.Val520Phe AF508, AF508lAF508, M470V (p),Q493X, Q493WAF508,V520F. Login to comment 76 ABCC7 p.Gly551Asp V52OF/AFS08, 1717- 1G>A, 1717-lG>A/AF508 G551D. Login to comment 77 ABCC7 p.Arg553* ABCC7 p.Gly542* R553X, G542X. Login to comment 78 ABCC7 p.Glu831* ABCC7 p.Arg560Thr ABCC7 p.Ser977Pro ABCC7 p.Val562Leu ABCC7 p.Arg764* ABCC7 p.Tyr563Asn ABCC7 p.Glu827* ABCC7 p.Arg709* ABCC7 p.Lys716* ABCC7 p.Tyr917Cys R560T, 1811+1G>C V562L, Y563N, 1898+lG>T 2143delT E827X R709X, K716X R764X E831X, W846X1,2711delT 2789+5G>A Y917C S977P. Login to comment 79 ABCC7 p.Arg1162* ABCC7 p.Arg1158* ABCC7 p.Asp1152His ABCC7 p.Gly1123Arg ABCC7 p.Leu1059* 3120G>A 11027T,3130de115 L1059X G1123R D1152H 3659delC, 3849G>A, 3849+4A>G, R1158X, R1162X. Login to comment 82 ABCC7 p.Leu1254* L1254X, 3898insC. Login to comment 83 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Arg1283Met W1282X, R1283M N1303K. Login to comment 84 ABCC7 p.Gln1412* ABCC7 p.Ser1235Arg ABCC7 p.Glu1371* ABCC7 p.Ser1196* ABCC7 p.Gln1313* 4048insCC, Q1313X E1371X Q1412X 4279insA 4521 G or A (p) S1196X, S1235R 10-60 20-80 20-80 0-50 20-70 20-70 20-70 20-70 20-70 10-60 20-70 20-70 0-50 20-80 20-80 20-80 20-80 20-70 20-70 20-80 20-80 20-70 20-70 20-70 20-70 20-70 20-70 20-80 20-70 20-70 40-80 75 75 150 75 150 150 150 75 150 150 150 75 150 75 75 75 150 150 150 95 150 150 150 150 150 150 150 150 150 150 150 9 9 4.5 6.5 4 4 4.5 7.5 4 5 4 7.5 4 7 7 7 4 4 4 6.5 4 4 3.5 4 4 5 4 6.5 4.5 4 4 ^Allmutationshave been reported to the CysticFibrosis Genetic AnalysisConsortium.The five polymorphisms are marked with a p in parenthesis. Login to comment 86 ABCC7 p.Val562Leu DISCUSSIONa severe mutation, and as the patient has a moderate disease pathology V562L can probably be A cohort of 206 CF patients from Northern Ire- classified as a mild CF defect. Login to comment 89 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg560Thr G551D (5.1%), R117H (4.1%), R560T (2.9%), HUGHESET AL. Login to comment 96 ABCC7 p.Val562Leu Characterisation of mutation V562L in exon 12 of the CFTR gene. Login to comment 97 ABCC7 p.Val562Leu (a) DGGE analysis of PCR products from normal controls (N)and a CF patient (1)heterozygous for V562L. Login to comment 98 ABCC7 p.Val562Leu (b) Automated sequence profile of mutation V562L, where an asterisk marks the G to C substitution, and below the normal allele. Login to comment 99 ABCC7 p.Gly542* G542X (2.2%), 621+1G>T (2.2%), and A1507 (1.7%); the next seven mutations were found in two or three chromosomes, with the remaining 16 mutations being identified only once. Login to comment 105 ABCC7 p.Val562Leu Two of these mutations, M1I (G>T) and V562L are novel and 13 others had not previously been found here (Table 1). Login to comment 108 ABCC7 p.Arg117His ABCC7 p.Gly542* There were four mutations, R117H, AF508, AI507, and G542X, on 11 CF alleles that were missed due to poor PCR amplification in their original screening methods (Table 1) but were detected using DGGE. Login to comment 110 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr Analysis of three intragenic CFTR microsatellites demonstratedthat all R117H and R560T alleles share the same respective haplotype: 16(IVS8CA)- 30(IVS17bTA)- 13(IVSl7bCA) for R117H and 16-07-17for R560T. Login to comment 120 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg560Thr A commercially available reverse dotblot assay (Innogenetics) is presently used in our laboratory for routine screening of eight CF mutations, of which seven are found in this population; AF508, AI507, G551D, G542X, R553X, N1303K, and W1282X and account for 78% of CFTR defects with additional mutations R560T, 621+1G>T and Rl17H screened using individual assays. Login to comment