ABCMdb

PMID: 11523757

Dawson KP, Frossard PM
The S549R (T-->G) cystic fibrosis gene mutation.
J Trop Pediatr. 2001 Aug;47(4):196-8., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Ser549Arg Among the several mutations that have been described in exon 11 of the CFTR is S549R (T➝G). Login to comment 5 ABCC7 p.Ser549Arg Serine is a highly conserved amino acid in this important binding domain and its replacement by an arginine residue is expected to result in a severe chloride dysfunction and hence severe clinical disease.4 S549R is defined as a Class II mutation.5-8 These are associated with defective protein processing. Login to comment 12 ABCC7 p.Ser549Arg The existence of the mutation S549R (T➝G), was first reported to the Cystic Fibrosis Genetic Analysis Consortium on 9th February 1990 by Kerem and Tsui.2 The individual who carried the CF chromosome was a non-Ashkenazi Jewish patient from Morocco who also carried the ∆F508 mutation on the other allele.4 Further reference to this and one other Moroccan patient was made by Kerem, et al.9 who studied cystic fibrosis mutations in Jewish communities. Login to comment 14 ABCC7 p.Ser549Arg S549R was found only in these two patients from Morocco and it thus accounted for 6 per cent of the identified Jewish CF patients from that country. Login to comment 15 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Ile There have been four separate mutations described in codon 549, namely S549R (A➝C), S549I, S549R (T➝G), and S549N2 (codons = triplet codes for each amino acid). Login to comment 16 ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn A study of 27 177 CF chromosomes from 29 European and three north African countries showed that of the 272 mutations examined, S549R occurred on 12 occasions (0.04 per cent) and the S549N on 16 occasions (0.059 per cent). Login to comment 17 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg Interestingly, despite its general rarity, the S549R mutation accounted for 2.6 per cent of all mutations in Algeria.3 However, a recent detailed study of 10 Algerian CF families revealed no patients with a mutation on exon 11.10 Another important report in the literature regarding the S549R mutation is from Saudi Arabia. Login to comment 21 ABCC7 p.Ser549Arg However, El-Harith, et al.13 investigated 15 Arab children from 12 Occasional Review The S549R (T➝G) Cystic Fibrosis Gene Mutation by K. P. Dawson and P. M. Frossard Departments of Paediatrics and Pathology, Faculty of Medicine and Health Sciences, UAE University,Al Ain, United Arab Emirates Correspondence: Professor K. P. Dawson, Chairman, Department of Paediatrics, Faculty of Medicine and Health Sciences, PO Box 17666, Al Ain, United Arab Emirates. Login to comment 26 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg No examples of S549R were detected and it is of significance that the families studied were all from the eastern region from where the one previous Saudi patient with S549R had been identified. Login to comment 27 ABCC7 p.Ser549Arg While studying patients with CF in the United Arab Emirates (UAE), it became apparent that the otherwise common CF mutation, ∆F508, was mostly found in those belonging to the minority Baluch ethnic group, while it was absent in the majority Bedouin population.14 Overall in the UAE, those who are homozygous for the mutation S549R (T➝G) account for over 90 per cent of all patients with CF. Login to comment 28 ABCC7 p.Ser549Arg ABCC7 p.Arg1158* Only one example of a heterozygote has been encountered and this patient had a mild phenotype and a genotype R1158X/S549R (T➝G). Login to comment 29 ABCC7 p.Asn1303Lys Sporadic examples of other mutations occur, such as homozygous examples of N1303K. Login to comment 30 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg The study of 15 Bedouin families with CF revealed that they were all homozygous for the S549R (T➝G) mutation.14 In a genotype-phenotype correlation with assessment based upon 20 outcome variables, it was apparent that in the homozygous state this mutation leads to a severe disease presentation with pancreatic insufficiency, early severe lung disease, and early colonization with Pseudomonas aeruginosa.15 Further radiological assessment of this group confirmed the association of extreme lung disease and rapid pulmonary decline in those patients homozygous for the mutation.16 To establish the carrier rate of the S549R (T➝G) mutation in the UAE, a sample of 400 unrelated UAE nationals was examined. Login to comment 31 ABCC7 p.Ser549Arg The estimated frequency of carriers of S549R (T➝G) was determined as 1:100.17 The question then arose as to whether this was a unique finding in the UAE or whether the mutation was to be found commonly in the neighbouring Arab countries. Login to comment 35 ABCC7 p.Ser549Arg The debate then arises as to the comparative severity associated with S549R (T➝G) and the ∆F508 mutation. Login to comment 37 ABCC7 p.Ser549Arg We concluded that the clinical severity of S549R (T➝G) at least equates to that of homozygous ∆F508 individuals in a UAE setting (unpublished observation). Login to comment 39 ABCC7 p.Ser549Arg Thus, the data from eastern Arabia points to S549R (T➝G) being a mutation causing severe clinical disease and probably as severe as found in CF. Login to comment 47 ABCC7 p.Ser549Arg The -102T➝A mutation was found on the same allele with the mutation S549R (T➝G) in a compound heterozygote situation with ∆F508 in one female patient. Login to comment 48 ABCC7 p.Ser549Arg ABCC7 p.Ser945Leu A male patient had a compound heterozygote S549R (T➝G)/S945L with -102T➝A promoter mutation. Login to comment 50 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg This contrasted with the prior report that S549R was associated with severe disease.1 The French patients were not, however, homozygous for S549R, but one had a severe mutation, ∆F508, in a compound heterozygote situation. Login to comment