ABCMdb

PMID: 8825494

Zielenski J, Tsui LC
Cystic fibrosis: genotypic and phenotypic variations.
Annu Rev Genet. 1995;29:777-807., [PubMed]

Sentences

No. Mutations Sentence Comment

545 ABCC7 p.Gly542* Even the second most common mutation (G542X) has only a relative frequency of about 2.4% (Table 1). Login to comment 551 ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* ABCC7 p.Arg560Thr FIBROSIS Table 1 Most common CFTR mutations in the world Name of Mutation �F508 0542X 0551D NI303K WI282X R553X 621 + 10 � T 1717-10 � A RI17H R1162X R347P 3849 + IOkbC � T �1507 394delTT 085E R560T A455E 1078deiT 2789 + SO � A 3659deiC R334W 1898 + 10 � T 711 + 10 --. Login to comment 552 ABCC7 p.Ser549Asn T 2183AA --.0 3905insT S549N 2184deiA Q359K1T360K MllOlK YI22X 1898 + 50 --. Login to comment 574 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* ABCC7 p.His199Tyr ABCC7 p.Leu558Ser On the other hand, many mutations (R117H, H199Y, R334W, R347P, R553X; L558S, 3272-26A�G, 3849+lOkbC�T, R1162X) are found associated with two or three haplotypes that cannot be possibly derived from each other by simple molecular mechanisms (58, 124). Login to comment 580 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* For example, many different microsatellite alleles have been found associated with AF508, G542X, and N1303K (123). Login to comment 586 ABCC7 p.Arg553Gln The fIrst example is R553Q, which is found on an allele carrying . Login to comment 590 ABCC7 p.Arg117His In another example, the clinical presentation of the missense mutation R117H can apparently be modulated by the length of a polythymidine tract upstream of the 3' splice site of intron 8 (101). Login to comment 593 ABCC7 p.Ser549Asn ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Arg553Gln ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Arg297Gln ABCC7 p.Ala800Gly ABCC7 p.Arg75* ABCC7 p.Gly628Arg ABCC7 p.Leu619Ser ABCC7 p.Leu88* ABCC7 p.Ser912Leu Not surprisingly, Rl17H is associated with CF only when the allele also contains Table 2 Examples of complex alleles in the CfTR gene Principal Second site mutationa Location alteration Location Reference R75X exon 3 125G --.. C promoter 57 405 + IG --.. A intron 3 3030G --.. A exon 15 57 R1l7H exon 4 129G --.. C promoter 203 RI17H exon 4 IVS8 : 5T or 7T intron 8 101 R297Q exon 7 IVS8 : 5T or 7T intron 8 60 aF508 exon 10 R553Q exon II 59 aF508 exon 10 1I027T exon I7a 57 8F508 exon 10 deletion of D7S8 500 kb 3' of 186 CfTR S549N exon II R75Q exon 3 205a L619S exon 13 1716G � A exon 10 57 G628R (G � C) exon 13 SI235R exon 19 47 2184insA exon 13 IVS:5T exon 9 J Zielenski, J Bal, 0 Markiewicz, L-C Tsui, unpublished data A800G exon 13 IVS8 : 5T or 7T intran 8 31 S912L exon 15 GI244V exon 20 149 GlO69R exon 17b L88X exon 3 149 3732deiA exon 19 Kl200E exon 19 70 3849 + IOkbC � intron 19 R668C exon 13 57 T SI251N exon 20 F508C exon 10 94 The status of principal mutation may not be clear in every case; e.g. G628R(G --> C) vs S1235R. Login to comment 595 ABCC7 p.Arg297Gln RI17H in combination with 5T can apparently produce only -40% of the CFfR transcript in full-length mRNA, whereas RI17H with 7T gives -90% (83), A similar modulating effect has been observed for R297Q, which can be associated with either 5T or 7T (60). Login to comment 596 ABCC7 p.Trp1282* Finally, variable mRNA splicing has been shown for W1282X. Login to comment 597 ABCC7 p.Trp1282* Although the W1282X-bearing transcripts are often rapidly degraded, some CF patients can apparently retain the mutant mRNA at a much higher level (160). Login to comment 602 ABCC7 p.Arg75Gln One example is R75Q, which was previously thought to be a benign polymorphism because it was found on both "normal" and CF alleles. Login to comment 603 ABCC7 p.Arg75Gln In one study R75Q was detected in six CF patients (205a). Login to comment 605 ABCC7 p.Ser549Asn ABCC7 p.Arg75Gln The one patient who showed severe CF disease was found to harbor a known CF mutation (S549N) in the allele carrying R75Q. Login to comment 606 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln Other mutations may therefore be present in those R75Q alleles that are associated with CF, but it is of interest that all R75Q alleles are associated with the same DNA marker haplotype and the 7T variant in intron 8. Login to comment 607 ABCC7 p.Arg75Gln Moreover, R75Q may be a borderline mutation whose disease association is dependent on extragenic factor(s). Login to comment 628 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* This strategy may also be applied to patients with other Normal II III IV V No synthesis Block in Block in Altered Reduced processing regulation conductance synthesis Nonsense Missense G542X Missense Missense Missense A455E Frameshift N1303K G551D R117H 394deiTT AA deletion Alternative L1F508 R347P splicing Splice junction 1717-1G-->A 3849+1OkbC-->T Figure 3 Molecular consequence of different classes ofCF mutations. Login to comment 629 ABCC7 p.Gly480Cys FrnROSIS mutations of this class, such as G480C, which also appear to have appreciable cAMP-responsive chloride channel activity after reaching the plasma membrane (163). Login to comment 631 ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro The range of effects of dysregulation of the channel includes those with a severe lack of function (such as that for G551D), reduced response to ATP stimulation (S1255P), and slight reduction of absolute activity (G551S, G1244E, and G1349D) (7, 63). Login to comment 634 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly314Glu Examples of this group include R l 17H near TM2, G314E in TM5, and R334W and R347P in TM6. Login to comment 636 ABCC7 p.Arg117His While R117H alone appears to have relatively high activity, the allele associated with CF patients also has the inefficient splice variant (see section on Complex Alleles). Login to comment 644 ABCC7 p.Pro574His ABCC7 p.Ala455Glu Several missense mutations (e.g. P574H and A455E) are reasoned to have mild molecular consequence because they are found associated with pancreatic sufficiency-a mild phenotype (lOS). Login to comment 654 ABCC7 p.Ala455Glu One study based on a small number of PS patients suggests a correlation between A455E mutation and mild pulmonary presentation (76). Login to comment 679 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg75Gln Table 3 Atypical (non-CF) diseases associated with the CFTR gene Common manifestations Disease shared with CF CBAVD absence of vas deferens (bilateral CUAVD absence of vas deferens (unilateral) Obstructive azoospermia azoosperma Diffuse bronchiectasis abnormal dilatation of bronchi Bronchiectasis with elevated abnormal dilatation of bronchi and sweat CI- high levels of sweat chloride Allergic bronchopulmonary allergic asthma, tenacious sputum, aspergillosis mucus plugs Chronic pseudomonas bron- chronic sinusitis, nasal polyposis chitis Chronic bronchial abnormal mucous secretion hypersecretion Nasal polyposis nasal polyps Neonatal transitory hyper- high levels of immunoreactive tryp- trypsinemia sin (IRT) Fraction of patients with at least one CFTR mutation (%) Reference 80/\02 (78)" 31 51168 (75)' 207a 6/14 (43)b 1 1 8 8/17 (47)' 93 6/10 (6W 13 6/48 (l2.5)e 161 9/28 (32)" 136 5/16 (3 1)1 78 6/1 1 (54)e 1 19 2/10 (20)e 1 1 9 6/65 (9.2)f 65 7/1 12 (6.2)g 22 9/149 (6)f 106 • The numbers are based on comprehensive screening of CFfR mutations (including IVS8 : 5T) by a variety of methods; btesting of three mutations (�F508, RI I7H and R75Q; '-�F508, G55 1O, G542X, W1282X, N1303K, RI 17H and IVS8 : 5T;d direct sequencing of exons encoding NBFI; ' the most common CFTR mutations (unspecified); f �F508 only: "eight mutations (�F508, �I507, DlIOH, RII7H, 621 + IG .... T, N1303K, G5SID, and R553X). Login to comment 911 ABCC7 p.Arg297Gln A french CF family genetic analysis shows that the R297Q associated with the T7 allele in the intron 8 polypyrimidine track is not involved in the CF disease. Login to comment 977 ABCC7 p.Arg117His High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of vas deferens. N. Engl. J. Med 328:446- 47 79. Login to comment 993 ABCC7 p.Gly542* CFTR nonsense mutations G542X and WI282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Hum. Mol. Genet. 1 :542-44 85. Hamosh A, Trapnell BC, Zeitlin PL, Montrose RC, Rosenstein BJ, et aI. 1991. Login to comment 994 ABCC7 p.Arg553* ABCC7 p.Trp1316* Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis. Login to comment 1127 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Independent origins of cystic fibrosis mutations R334W, R347P, R I I 62X, and 3849+10kb CT provide evidence of mutation recurrence in the CFTR gene. Login to comment 1274 ABCC7 p.Trp1282* AssoCIation of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Login to comment 1278 ABCC7 p.Trp1282* Similar levels of mRNA from the W1282X and thedelta F508cysticfibrosisalleles, in nasal epithelial cells. Login to comment 1376 ABCC7 p.Gly542* A cystic fibrosis patient with 6F508, G542X and a deletion at the D7S8 locus. Login to comment 1404 ABCC7 p.Glu92* A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis. Login to comment 1409 ABCC7 p.Arg553* CFTR transcripts are undetectable in lymphocytes and respiratory epithelial cells of a CF patient homozygous for the nonsense mutation R553X. Login to comment 1433 ABCC7 p.Arg75Gln Haplotype analysis of chromosomes carrying the R75Q CFTR variant. Login to comment