ABCMdb

PMID: 1370365

Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y, Tal A, Seret H, Yaar L, Kerem E, et al.
Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease.
Am J Hum Genet. 1992 Jan;50(1):222-8., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Trp1282* One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Login to comment 10 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Together with the AF508 (23% in this group), G542X, N1303K, and 1717-1G-*A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Login to comment 11 ABCC7 p.Trp1282* ABCC7 p.Trp1282* Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the AF508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. Login to comment 12 ABCC7 p.Trp1282* In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. Login to comment 29 ABCC7 p.Gly542* ABCC7 p.Ser549Arg In a previous study of a small group of Israeli CF patients, four additional rare mutations (1717- 1G--A, G542X, S5491, and S549R) were found (Kerem et al. 1990b). Login to comment 56 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ser549Arg The G542X, S5491, S549R, N1303K, and 1717- 1G--A mutations were detected by PCR and subse- quent allele specific oligo nucleotide hybridization as described elsewhere (Kerem et al. 1990b; Osborne et al. 1991). Login to comment 64 ABCC7 p.Trp1282* One DNA alternation in exon 20 was found in 10 individuals; this was a G--A substitution at nucleotide position 3978, changing the Trp1282 codon to a stop codon (W1282X) and corresponding to a mutation described elsewhere (Vidaud et al. 1990). Login to comment 66 ABCC7 p.Trp1282* Of the remaining chromosomes carrying unidentified CF mutations, 63 were found to carry the W1282X mutation; 57 (90%) of these 63 were of Ashkenazi origin. Login to comment 67 ABCC7 p.Trp1282* Thus, the W1282X mutation is the most common mutation (60%) in the Ashkenazi Jewish patient population (table 1). Login to comment 69 ABCC7 p.Trp1282* The PCR product (473 bp long) has two MnO sites, one of which is destroyed by the W1282X mutation. Login to comment 70 ABCC7 p.Trp1282* Digestion of normal DNA (N) reveals three bands: 178, 172, and 123 bp in length. DNA digestion of homozygous for the W1282X mutation (M) reveals two bands: 301 and 172 bp in length. DNA digestion ofheterozygotes for the mutation (H) reveals four bands: 301, 178, 172, and 123 bp. Login to comment 72 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Gly542* patients screened, 16 (15 Ashkenazi and 1 Arab) were homozygous for W1282X, 22 (20 Ashkenazi, 1 Sephardic, and 1 from an unclassified origin) were heterozygous for W1282X and AF508, 2 (Ashkenazi) patients were heterozygous for W1282X and G542X, and 11 patients were heterozygous for W1282X and an as yet unidentified mutation. Login to comment 73 ABCC7 p.Trp1282* DNA marker haplotype analysis for informative families showed that chromosomes carrying the W1282X mutation were associated with haplotype B at the H2.3A/ TaqI and El1PstI loci. Login to comment 76 ABCC7 p.Asn1303Lys This was a G--C substitution at nucleotide position 4041, changing the 1303 codon to Lysin (N1303K) and corresponding to a mutation described elsewhere (Osborne et al. 1991). Login to comment 77 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Hence, together with AF508, G542X, N1303K, and 1717-1G--A, 92% of the CF chromosomes could be identified in Jewish patients of Ashkenazi origin. Login to comment 79 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ser549Arg Therefore, for assessment of the severity of the W1282X mutation, it would have been appropriate to compare patients homozygous for the W1282X mutation with patients homozygous for the AF508 mutation and with patients heterozygous for Table I Analysis of Mutation Frequencies Identified in 97 Israeli CF Patients JEWISH PATIENTS ARAB Ashkenazim Sepharadim Unclassified PATIENTS No. of chromosomes sampled.... 95 51 8 40 W1282X (no. [%]) .................. 57 (60) 1 (2) 3 (38) 2 (5) AF508 (no. [%])..................... 21 (23) 18 (35) 2 (25) 10 (25) G542X (no. [%]).................... 4 (4) 2 (4)0 2 (5) N1303K (no. [%]) .................. 4 (4) 0 0 2 (5) 1717-1G-A (no. [%]) ............. 1 (1) 0 0 1 (3) S5491 (no. [%])...................... 0 0 0 2 (5) S549R (no. [%])..................... 0 1 (2) 2 (25) 2 (5) Total mutations (no. [%])...... 87 (92) 22 (43) 7 (88) 21 (53) both mutations. Login to comment 81 ABCC7 p.Trp1282* ABCC7 p.Trp1282* Therefore, the clinical data for the patients homozygous for the W1282X mutation were compared with those for the heterozygous patients carrying both the AF508 mutation and the W1282X mutation. Login to comment 83 ABCC7 p.Trp1282* ABCC7 p.Trp1282* Three patients homozygous for the W1282X mutation died (at ages 0.5, 2, and 12 years), and three patients heterozygous for both AF508 and W1282X died (at ages 0.25, 5, and 23 years). Login to comment 90 ABCC7 p.Trp1282* ABCC7 p.Trp1282* This indicates similar severity of pulmonary function in patients either homozygous for W1282X or heterozygous for the W1282X and AF508 mutations, as compared with patients homozygous for the AF508 mutation. Login to comment 91 ABCC7 p.Trp1282* ABCC7 p.Gly542* Two patients were heterozygous for two different termination mutations, W1282X and G542X. Login to comment 92 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* One Table 2 Comparison of Clinical Characteristics and Pulmonary Function: CF Patients Homozygous for W1282X Mutation versus CF Patients Heterozygous for W1282X and AF508 Mutations W1282X/W1282X W1282X/AF508 No. of patients sampled ............... 16 22 No. (%) with meconium ileus ....... 6 (37) 6 (27) Age at diagnosis (years) ............... .9 ± 2.6 .6 ± .8 Sweat chloride (mmol\liter) .......... 113 ± 12 109 ± 11 Current age (years) ..................... 9.3 ± 7.5 11.6±7.5 Current weight (%-ile) ................. 17 ± 17 28 ± 21 Current height (%-ile) ................. 29 ± 29 27 ± 24 FEV, (% predicted) .................... 64 ± 27(n = 11) 69 26(n = 12) FEV2575 (% predicted) ................ 32 ± 20(n = 11) 52 ± 36(n = 12) NOTE. Login to comment 101 ABCC7 p.Trp1282* In the present study, we have described the most common CF mutation among Ashkenazi Jews, W1282X, accounting for 60% of the CF chromosomes in the studied group. Login to comment 103 ABCC7 p.Trp1282* The W1282X mutation has been found to be rare in other, non-Jewish different patient groups; in a worldwide survey, only 1.6% ofthe CF chromosomes were found to carry this mutation (Cystic Fibrosis Genetic Analysis Consortium, unpublished data). Login to comment 106 ABCC7 p.Trp1282* W1282X is a termination mutation. Login to comment 108 ABCC7 p.Trp1282* ABCC7 p.Trp1282* Thepresent study showsthatpatients homozygous for W1282X had disease severity similar to that of patients heterozygous for W1282X and AF508. Login to comment 115 ABCC7 p.Trp1282* Since pulmonary function inpatients carryingsevere CF mutations (i.e., AF508 and W1282X) have high variability, it is difficult to conclude whether the milder form of pulmonary disease shown in these two patients is genetically determined. Login to comment