ABCMdb

PMID: 9439669

Casals T, Ramos MD, Gimenez J, Larriba S, Nunes V, Estivill X
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.
Hum Genet. 1997 Dec;101(3):365-70., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Arg851Leu ABCC7 p.Phe1074Leu ABCC7 p.Gln1281* ABCC7 p.Thr582Arg ABCC7 p.Gly85Val ABCC7 p.Glu692* Among these we have detected seven novel CFTR mutations, including four missense (G85V, T582R, R851L and F1074L), two nonsense (E692X and Q1281X) and one splice site mutation (711+3A→T). Login to comment 4 ABCC7 p.Arg851Leu ABCC7 p.Phe1074Leu ABCC7 p.Gln1281* ABCC7 p.Thr582Arg ABCC7 p.Gly85Val ABCC7 p.Glu692* Mutations G85V, T582R, R851L, E692X and Q1281X are severe, with lung and pancreatic involvement; 711+3A→T could be responsible for a pancreatic sufficiency/insufficiency variable phenotype; and F1074L was associated with a mild phenotype. Login to comment 13 ABCC7 p.Arg851Leu ABCC7 p.Phe1074Leu ABCC7 p.Gln1281* ABCC7 p.Thr582Arg ABCC7 p.Gly85Val ABCC7 p.Glu692* Among these are seven novel CFTR mutations, including four missense (G85V, T582R, R851L and F1074L), two nonsense (E692X and Q1281X) and one splice site mutation (711+3A→T). Login to comment 21 ABCC7 p.Gly542* The ∆F508 (Rommens et al. 1990) and G542X (Kerem et al. 1990; Gasparini et al. 1992) mutations were analysed in all patients as they are the most common mutations in the population, 50.6% and 8.0%, re- Teresa Casals · Maria D. Ramos · Javier Giménez · Sara Larriba · Virginia Nunes · Xavier Estivill High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes Hum Genet (1997) 101:365-370 (c) Springer-Verlag 1997 Received: 3 July 1997 / Accepted: 20 August 1997 ORIGINAL INVESTIGATION T. Casals · M. D. Ramos · J. Giménez · S. Larriba · V. Nunes · X. Login to comment 31 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg1066Cys ABCC7 p.Gln890* Only ten mutations have a frequency of 1% and above: ∆F508 (53.2%), G542X (8.4%), N1303K (2.6%), 1811+1.6kbA→G (1.8%), 711+1G→T (1.7%), R1162X and R334W (1.6%), R1066C, 1609delCA and Q890X (1.0%). Login to comment 33 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Glu585* ABCC7 p.Leu206Trp ABCC7 p.Gly85Glu ABCC7 p.Arg1158* ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Lys710* ABCC7 p.Gln890* ABCC7 p.Val232Asp ABCC7 p.Trp1089* ABCC7 p.Leu558Ser ABCC7 p.Ala1006Glu ABCC7 p.Arg851* ABCC7 p.Gly673* ABCC7 p.Arg709* ABCC7 p.Leu571Ser ABCC7 p.Ala561Glu ABCC7 p.Gln1313* Eight mutations have frequencies 366 Table 1 Seventy-five CFTR mutations identified in 640 Spanish families with cystic fibrosis (CF) Mutation Exon/intron CF alleles % ∆F508 E.10 681 53.20 G542X E.11 108 8.43 N1303K E.21 34 2.65 1811+1.6kbA→Ga I.11 24 1.87 711+1G→T I.5 22 1.71 R1162Xa E.19 21 1.64 R334Wa E.7 21 1.64 R1066C E.17b 14 1.09 1609delCAa E.10 13 1.01 Q890X E.15 13 1.01 G85E E.3 12 0.94 712-1G→Ta I.5 11 0.86 2789+5G→A I.14b 11 0.86 ∆I507 E.10 10 0.78 W1282X E.20 10 0.78 2869insGa E.15 9 0.70 L206W E.6a 7 0.54 R709X E.13 7 0.54 621+1G→T I.4 6 0.47 3272-26A→G I.17a 6 0.47 R347H E.7 5 0.39 2183AA→G E.13 5 0.39 K710X E.13 5 0.39 2176insC E.13 5 0.39 3849+10kbC→T I.19 5 0.39 P205Sa E.6a 4 0.31 1078delT E.7 4 0.31 R553X E.11 4 0.31 G551D E.11 4 0.31 1812-1G→Aa I.11 4 0.31 CFdel#1a E.4-7/11-18 4 0.31 V232D E.6a 3 0.23 936delTAa E.6b 3 0.23 1717-8G→A I.10 3 0.23 1949del84 E.13 3 0.23 W1089X E.17b 3 0.23 R347P E.7 3 0.23 del E.3a E.3 2 0.16 R117H E.4 2 0.16 L558S E.11 2 0.16 A561E E.12 2 0.16 2603delT E.13 2 0.16 Y1092X E.17b 2 0.16 Q1100Pa E.17b 2 0.16 M1101K E.17b 2 0.16 delE.19a E.19 2 0.16 G1244E E.20 2 0.16 P5La E.1 1 0.08 Q30Xa E.2 1 0.08 G85Va E.3 1 0.08 E92Ka E.4 1 0.08 A120Ta E.4 1 0.08 I148T E.4 1 0.08 711+3A→Ta I.5 1 0.08 H199Y E.6a 1 0.08 875+1G→A I.6a 1 0.08 Table 1 (continued) Mutation Exon/intron CF alleles % 1717-1G→A I.10 1 0.08 L571S E.12 1 0.08 T582Ra E.12 1 0.08 E585X E.12 1 0.08 1898+3A→G I.12 1 0.08 G673X E.13 1 0.08 E692Xa E.13 1 0.08 R851X E.14a 1 0.08 R851La E.14a 1 0.08 A1006E E.17a 1 0.08 L1065Ra E.17b 1 0.08 F1074La E.17b 1 0.08 R1158X E.19 1 0.08 3667del4a E.19 1 0.08 3860ins31a E.20 1 0.08 3905insT E.20 1 0.08 4005+1G→A I.20 1 0.08 Q1281Xa E.20 1 0.08 Q1313X E.21 1 0.08 Known mutations (75) 1155 90.23 Unknown mutations 125 9.77 a Mutations discovered by the CF group of the Medical and Molecular Genetics Centre - IRO, Barcelona, Spain that range between 0.5% and 0.9%, representing 6.0% of the CF chromosomes. Login to comment 36 ABCC7 p.Leu1065Arg Segregation studies of the mutations in the CF families allowed us to identify one case of a de novo mutation (L1065R) (Casals et al. 1997). Login to comment 38 ABCC7 p.Arg1162* ABCC7 p.Arg1162* In two cases, the direct analysis of mutation R1162X based on the microsatellite haplotype showed a homozygous R1162X pattern in the patient, where only one parent was heterozygous for this mutation and the other was homozygous for the normal allele. Login to comment 41 ABCC7 p.Gly85Val ABCC7 p.Gly85Val New mutations G85V An abnormal DGGE pattern in exon 3 due to the nucleotide change G→T at position 386 of CFTR determines the missense mutation G85V (glycine to valine). Login to comment 43 ABCC7 p.Gly542* ABCC7 p.Gly85Val The G85V mutation was identified in a patient who carries the G542X mutation on the maternal CF allele. Login to comment 45 ABCC7 p.Gly85Val At 18 years of age he presents a severe CF phenotype with pancreatic insufficiency (PI) and a FEV1 of 32%, suggesting that G85V is a severe mutation. Login to comment 46 ABCC7 p.Gly85Glu Another mutation that affects the same codon, mutation G85E, is involved in a milder clinical presentation of CF with late-onset pancreatic sufficiency (PS) in 70% of cases (Vazquez et al. 1996). Login to comment 49 ABCC7 p.Arg334Trp The CF patient presented the R334W mutation on the paternal chromosome. Login to comment 54 ABCC7 p.Thr582Arg ABCC7 p.Thr582Arg T582R An abnormal DGGE pattern in exon 12 was due to a C → G change at position 1877 of CFTR, which produced the missense mutation T582R (threonine to arginine). Login to comment 55 ABCC7 p.Thr582Arg The 1837-13 CFTR microsatellite haplotype associated with T582R is unique in our CF patient population. Login to comment 56 ABCC7 p.Arg851Leu ABCC7 p.Phe1074Leu ABCC7 p.Gln1281* ABCC7 p.Thr582Arg ABCC7 p.Gly85Val ABCC7 p.Glu692* The patient carries the 1609delCA mutation on the paternal chromo- 367 Table 2 Seven new mutations and three DNA variants in the CFTR gene (IVS intervening sequence, DGGE denaturing gradient gel electrophoresis, SSCA single-strand conformation analysis) Mutations Exon/ CFTR Haplotype IVS Detection intron domain method 8CA 17bTA 17bCA G85V E.3 TM1 17 7 17 DGGE 711+3A→T I.5 - 15 7 17 DGGE T582R E.12 NB1 18 37 13 DGGE E692X E.13 R 16 46 13 SSCA R851L E.14a - 23 21 19 DGGE F1074L E.17b - 17 31 13 DGGE Q1281X E.20 NB2 16 28 13 DGGE Variants 406-112A/T I.3 - - SSCA 3850-129T/C I.19 - - DGGE 741C/T E.6a - - SSCA Fig.1 a Multiplex denaturing gradient gel electrophoretic analysis for exons 8, 5 and 18 of the CFTR gene. Login to comment 60 ABCC7 p.Thr582Arg Since the patient was diagnosed at a late age, it is likely that mutation T582R causes a milder CF phenotype. Login to comment 61 ABCC7 p.Glu692* ABCC7 p.Glu692* E692X The SSCA screening for exon 13 detected a G→T nucleotide change at position 2206 of CFTR, which gives rise to the nonsense mutation E692X (glutamic acid to the TAG stop codon; Fig.2). Login to comment 64 ABCC7 p.Arg851Leu ABCC7 p.Arg851Leu R851L An abnormal pattern for DGGE of exon 14a detected the missense mutation R851L (arginine to leucine) due to a nucleotide change, G→T, at position 2684 of CFTR. Login to comment 65 ABCC7 p.Arg851Leu R851L was observed in a carrier father whose two sons died due to CF. Login to comment 68 ABCC7 p.Phe1074Leu ABCC7 p.Phe1074Leu F1074L The F1074L missense mutation (phenylalanine to leucine) due to the nucleotide change T→A at position 3354 in exon 17b of CFTR was observed by DGGE analysis. Login to comment 69 ABCC7 p.Phe1074Leu F1074L is associated with microsatellite haplotype 17-3113 and the mutation was observed in only one family in which the three carrier brothers presented a mild phenotype. Login to comment 71 ABCC7 p.Phe1074Leu ABCC7 p.Phe1074Leu Although we have not yet identified the second mutation in this family, we have found F1074L in a congenital bilateral absence of the vas deferens (CBAVD) patient in association with a severe mutation (T. Casals, unpublished data), further confirming the mild effect of F1074L. Login to comment 72 ABCC7 p.Gln1281* ABCC7 p.Gln1281* Q1281X The DGGE analysis of exon 20 identified a C→T change at position 3973 of CFTR, leading to the nonsense mutation Q1281X (glutamine to the TAG stop codon). Login to comment 73 ABCC7 p.Gln1281* The Q1281X mutation is associated with microsatellite haplotype 16-28-13 and has been found in a CF patient with the ∆F508 mutation on the maternal CF allele. Login to comment 80 ABCC7 p.Lys710* ABCC7 p.Glu692* 368 Fig.2 a Single-strand conformation analysis of exon 13a of the CFTR gene with three abnormal patterns: lane 4 (1949del84), lane 5 (the new mutation E692X) and lane 6 (K710X). Login to comment 81 ABCC7 p.Glu692* b Sequencing analysis of the sample in lane showed the change C → A, which alters the glutamic acid at position 692 to a stop codon (E692X) Discussion A geographical distribution analysis of more than 200 CF mutations in several European populations has detected that the Mediterranean region has the highest level of mutation heterogeneity for CF (Estivill et al. 1997). Login to comment 87 ABCC7 p.Gln1281* ABCC7 p.Thr582Arg ABCC7 p.Gly85Val ABCC7 p.Glu692* However, from the information obtained here, mutations G85V, T582R, E692X and Q1281X can be considered as severe, with lung and pancreatic involvement. Login to comment 88 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp For the patient with the 711+3A→T/R334W genotype it is difficult to predict the severity of the 711+3A→T mutation as R334W causes a PS/PI variable phenotype; since two brothers of this patient, also with PS, died at childhood, other genetic factors may explain the clinical variability in this family, as we reported previously (Estivill et al. 1995). Login to comment 89 ABCC7 p.Arg851Leu The amino acid change in the missense mutation R851L, for which two deceased CF brothers were probably homozygous, should result in a severe mutation. Login to comment 90 ABCC7 p.Phe1074Leu Finally, F1074L was detected in three brothers of the same CF family with a mild phenotype. Login to comment 92 ABCC7 p.Arg851Leu ABCC7 p.Phe1074Leu ABCC7 p.Thr582Arg ABCC7 p.Gly85Val While microsatellite haplotypes of mutations G85V and F1074L were also associated with several other mutations, the haplotypes associated with 711+3A→T, T582R and R851L are unique in the CF population studied here, providing a useful tool for mutation analysis (Morral et al. 1996). Login to comment