ABCMdb

PMID: 7532150

Casals T, Bassas L, Ruiz-Romero J, Chillon M, Gimenez J, Ramos MD, Tapia G, Narvaez H, Nunes V, Estivill X
Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: in 50% of cases only one CFTR allele could be detected.
Hum Genet. 1995 Feb;95(2):205-11., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Lys1060Thr ABCC7 p.Lys1060Thr A second new mutation was found in exon 17b, viz., an A--~C substitution at position 3311, changing lysine to threonine at codon 1060 (K1060T). Login to comment 9 ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp Only three CBAVD patients were found with more than one CFFR mutation (AF508/L206W, AF508/R74W + D 1270N, R 117H/712-1G--~T), highlighting L206W, R74W/ T. Casals -M. Chill6n. Login to comment 10 ABCC7 p.Arg117His ABCC7 p.Asp1270Asn J. Gimrnez 9M. D. Ramos 9V. Nunes X. Estivill (Ig~l) Molecular Genetics Department, Cancer Research Institute, Hospital Duran i Reynals, Autovfa de Castelldefels Km. 2.7, L'Hospitalet de Llobregat, E-08907 Barcelona, Catalonia, Spain L. Bassas 9J. Ruiz-Romero 9H. Narwiez Andrology Department, I.U.N.A., Fundaci6 Puigvert, Barcelona, Catalonia, Spain G. Tapia Pediatrics Department, Hospital de Sant Pau, Barcelona, Catalonia, Spain D1270N, and R117H as benign CF mutations. Login to comment 41 ABCC7 p.Gly542* Genomic DNA from CBAVD and CUAVD subjects was first analyzed for the two most common mutations in the Spanish population, viz., AF508 and G542X (Casals et al. 1993). Login to comment 56 ABCC7 p.Gly542* ABCC7 p.Gly542* The two most frequent CF mutations in the Spanish population (AF508 and G542X) were found on 14 chromosomes (10 AF508 and 4 G542X). Login to comment 59 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Leu206Trp Direct sequencing of these two abnormal fragments identified mutation R ll7H, a known Table 1 Semen analysis of patients with CAVD, given as the mean (range) CBAVD CUAVD (n = 27) (n = 10) Sperm (x 106/ml) 0 10.6 (0-90) Seminal volume (ml) 0.9 (0.2-3.1) 2.5 (0.4 5.4) pH 6.7 (6.0-8.0) 7.3 (6.4-7.7) Fructose (retool/l) 2.6 (0-9) 10.3 (3-) '~Citrate (mmol/l) 77.5 (11-188) 48.6 (36-88) ~Reference values: fructose, 8 28 retool/l; citrate, 10 35 retool/1 Table 2 CFTR mutation analysis in 30 CBAVD and 10 CUAVD patients (CBAVD congenital bilateral absence of the vas deferens, CUAVD congenital unilateral absence of the vas deferens, ND not determined, - absence of mutations, RRI recurrent respiratory infection, R rhinitis, RS rhino-sinusitis, BR.ASTH bronchitis asthmatic) Table 3 Congenital malformations associated with CAVD in 40 patients 207 Patient Age Phenotype Sweat test Mutation Other clinical (years) (mEq/l) features 1 37 CBAVD 108 1677delTA 2 28 CBAVD 50 G542X 3 28 CBAVD 118 - 4 33 CBAVD 90 AF508/L206W RRI, R 5 26 CBAVD 118 R117H/712-1G-+T 6 42 CBAVD 66 - RS 7 31 CBAVD 170 AF508 R 8 27 CBAVD 100 AF508/R74W + D1270N RRI, R 9 32 CBAVD 74 AE115 RS 10 35 CBAVD 90 - Nasal polyps 11 33 CBAVD 78 KI060T RI, family history 12 45 CBAVD 150 R334W RS 13 42 CBAVD 60 - 14 40 CBAVD 110 R 1070W RS 15 29 CBAVD 110 G542X 16 37 CBAVD 80 R117H RI, RS, BR.ASTH 17 37 CBAVD 85 - Asthma 18 46 CBAVD 15 R1162X 19 37 CBAVD 110 AF508 RS, diarrhoea 20 42 CBAVD 45 2789+5G--)A RI 21 49 CBAVD 95 AF508 22 36 CBAVD 70 AF508 RRI, RS 23 42 CBAVD 90 - 24 15 CBAVD 150 AF508 25 26 CBAVD 60 - 26 39 CBAVD 100 AF508 RRI, RS 27 33 CBAVD 57 AF508 RRI 28 33 CBAVD 80 G542X 29 34 CBAVD 78 - 30 32 CBAVD 113 G542X 31 33 CUAVD ND AF508 RS, pancreatitis 32 37 CUAVD ND - 33 31 CUAVD 77 - BR.ASTH 34 39 CUAVD ND - 35 40 CUAVD 40 - 36 33 CUAVD 59 - 37 40 CUAVD 90 - 38 47 CUAVD 40 - RRI 39 39 CUAVD 50 - 40 35 CUAVD 100 - No. Login to comment 70 ABCC7 p.Arg117His Lane 2 corresponds to mutation R117H and lane 7to mutation zXE115 NORMAL AG G AG G A A1C00AC T C T A T CG It I II ii It I I I I I t i|t ~ tlo ktt I It I I I ! Login to comment 76 ABCC7 p.Lys1060Thr For the observed changes, we considered the strong association between mutations and CFTR microsatellite haplo- K1060T AaCTsor,~AcA~_ QA.,~ATaG .c ' {i a ;, ' ! Login to comment 83 ABCC7 p.Arg334Trp ABCC7 p.Leu206Trp The analysis of this specific mutation/haplotype association allowed us to identify mutations L206W (167-17), 712-1G-+T (23-31-13), R334W (17-46-13), and 2789 + 5G--->A (17-7-17), on one mutated chromosome each. Login to comment 86 ABCC7 p.Lys1060Thr ABCC7 p.Lys1060Thr One abnormal pattern in exon 17b was caused by an A--~C substitution at position 3311, changing lysine to threonine at codon 1060 (K1060T); this is a new missense mutation in the CFTR gene (Fig. 3). Login to comment 88 ABCC7 p.Arg1070Trp A second change in exon 17b corresponded to R1070W (M. Macek Jr., personal communication to CFGAC), which has not previously been detected in Spanish CF chromosomes (Chill6n et al. 1994b). Login to comment 89 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp Another abnormal DGGE fragment detected in exon 3 was the result of mutation R74W (Claustres et al. 1993); this mutation was found to be associated with mutation D1270N in exon 20 (Anguiano et al. 1992; C. F6rec and M. Claustres, personal communication). Login to comment 96 ABCC7 p.Leu206Trp One patient was heterozygous AF508/L206W and had recurrent pulmonary infection and rhinitis episodes from the age of 24. Login to comment 97 ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp Our data on Spanish CF patients with the mutation L206W (Claustres et al. 1993) suggest that L206W is a mild mutation associated with a benign CF phenotype (T. Casals, unpublished). Login to comment 98 ABCC7 p.Arg117His The second patient was heterozygous for mutations Rll7H/ 712-1G---)T, and had only a CBAVD phenotype, probably because of the benign mutation R117H (Dean et al. 1990). Login to comment 99 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp The third patient had AF508/R74W + D1270N, with clinical features of rhinitis and recurrent respiratory infections. Login to comment 100 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp We do not know which of the two mutations (R74W or D1270N, or both) is involved in the CBAVD phenotype. Login to comment 103 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Arg1070Trp ABCC7 p.Lys1060Thr In 13 cases, the mutations are known to be associated with severe CF (AF508, G542X, Rl162X and 1677delTA), whereas in five cases, the phenotypic effect of the mutation is still unknown (AEll5, K1060T, R334W, R1070W, and 2789 + 5G---)A); in one case (Rll7H), the mutation is known to result in mild CE Of these mutations, R334W seems to cause pancreatic insufficiency with a variable age of onset (X. Estivill, in press), whereas mutation 2789 + 5G--)A (W. E. Jr. High- smith, personal communication to the CFGAC) has frequently been found in adult CF patients and is probably involved in a mild phenotype (T. Casals et al. unpublished). Login to comment 116 ABCC7 p.Lys1060Thr The two new mutations detected here (AEll5 and K1060T) are located in transmembranic domains of CFTR, where it is well known that changes affect ion-channel transport (Cheng et al. 1990). Login to comment 119 ABCC7 p.Lys1060Thr For mutation K1060T, the lysine residue is conserved in the mouse, bovine, and Xenopus (Tucker et al. 1992), suggesting that this position in the second transmembrane domain might be more crucial. Login to comment 121 ABCC7 p.Lys1060Thr Although there is no doubt about the involvement of AE115 and K1060T in CBAVD, the genuine clinical significance of these two new mutations cannot be established, since only one mutation was detected in each individual. Login to comment 122 ABCC7 p.Lys1060Thr Further examples of mutations AE115 and K1060T should provide appropriate phenotype/genotype correlations. Login to comment 141 ABCC7 p.Gly542* In: Striver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 2649-2680 Casals T, Nunes V, Palacio A, Gimdnez J, Gaona A, Ibfifiez N, Morral N, Estivill X (1993) Cystic fibrosis in Spain: high frequency o1"mutation G542X in the Mediterranean coastal area. Login to comment 143 ABCC7 p.Pro205Ser Cell 63:827-837 Chill6n M, Casals T, Nunes V, Gimdnez J, Pdrez Ruiz E, Estivill X (1993) Identification of a new missense mutation (P205S) in the first transmembrane domain of the CFTR gene associated with a mild cystic fibrosis phenotype. Login to comment 144 ABCC7 p.Ala120Thr ABCC7 p.Gln30* Hum Mol Genet 10: 1741-1742 Chill6n M, Casals T, Gim6nez J, Nunes V, Estivill X (1994a) Analysis of the CFTR gene in the Spanish population: SSCP- screening for 60 known mutations and identification of four new mutations (Q30X, A120T, 1812-1G->A and 3667de14). Login to comment 150 ABCC7 p.Arg334Trp Lancet 336:512 Estivill X, Ortigosa L, P6rez-Frias J, Dapena J, Ferret J, Pefia J, Pefia L, Llevadot R, Nunes V, Cobos N, Vtizquez C, Casals T (1995) Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W, a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences. Login to comment 158 ABCC7 p.Glu92Lys Hum Mol Genet 7:1015-1022 Nunes V, Chillon M, D6rk T, Tiimmler B, Casals T, Estivill X (1993) A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype. Login to comment