ABCMdb

PMID: 11005149

Frossard PM, Abdelaziz SA, Hertecant J, Girodon E, Goossens M, Dawson KP
Mild clinical phenotype associated with R1158X/S549R(T-->G) CFTR genotype.
Clin Genet. 2000 Aug;58(2):147-9., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC7 p.Arg1158* All rights reser6ed Letter to the Editor Mild clinical phenotype associated with R1158X/S549R(TG) CFTR genotype To the Editor: Cystic fibrosis (CF) is due to DNA variations that modify the sequence, structure, function and/or expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (1). Login to comment 8 ABCC7 p.Ser549Arg Moreover, the clinical presentation associated with S549R homozygosity is quite homogeneous and shows an extreme degree and course of CF severity - at least as much as those associated with DF508 (5, 6). Login to comment 9 ABCC7 p.Ser549Arg ABCC7 p.Arg1158* We report here the identification of the first compound heterozygote patient in the UAE, who harbours mutations S549R/R1158X in his CFTR gene. Login to comment 35 ABCC7 p.Arg1158* Results indicate that AIM is a compound heterozygote harbouring mutation S549R(TG) in exon 11 of one CFTR allele, and nonsense mutation R1158X (7) in exon 19 of the other allele. Login to comment 39 ABCC7 p.Arg1158* Moreover, his R1158X/S549R(TG) CFTR genotype is associated with an atypically mild course of the disease. Login to comment 40 ABCC7 p.Arg1158* R1158X had originally been reported as a rare mutation, with, for example, one allele in Spain (8) and Portugal (9), and two alleles in southern France (10) and Canada (11). Login to comment 42 ABCC7 p.Arg1158* ABCC7 p.Arg1158* Genotype-phenotype correlations for this mutation have indicated that R1158X homozygosity underlies a very severe expression of CF (13) and that a patient with a DF508/R1158X genotype had experienced several complications (11). Login to comment 43 ABCC7 p.Arg1158* Thus, although a patient with an R1158X/S549R(TG) genotype could have been expected to present with severe clinical manifestations, we find here that it is not the case. Login to comment 45 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg1158* ABCC7 p.Arg1158* Indeed, Duarte et al. (9) have reported that a complex allele containing two mutations, R334W and R1158X, is associated with reduced levels of correctly processed mRNA, and that a patient with the complex genotype R334W-R1158X/DF508 presented with pancreatic sufficiency and an atypical course of CF. Login to comment 50 ABCC7 p.Arg1158* Although almost all of the previously analysed nonsense CFTR mutations have been associated with either considerable transcript reduction or production of aberrant transcripts (skipping) (16), an explanation for the mild phenotype might be that the transcript corresponding to the R1158X allele is stable and correctly spliced. Login to comment 51 ABCC7 p.Arg1162* Such a mechanism may be supported by the fact that there was no exon skipping or instability in the case of mutation R1162X in 3 unrelated patients (16). Login to comment 52 ABCC7 p.Arg1162* It has therefore been suggested that a non-standard decoding mechanism (e.g. readthrough) may contribute to alleviate the molecular consequences of the mutation (CF patients carrying R1162X have in fact milder pulmonary presentations). Login to comment 53 ABCC7 p.Arg1158* As the R1158X mutation is located 4 codons upstream from codon 1162, it could be associated with the same non-standard decoding mechanism that rescues the message and thus produces milder symptoms. Login to comment 77 ABCC7 p.Arg1158* Ronchetto P, Telleria Orriols JJ, Fanen P et al. A nonsense mutation (R1158X) and a splicing mutation (3849+4A----G) in exon 19 of the cystic fibrosis transmembrane conductance regulator gene. Login to comment 85 ABCC7 p.Arg334Trp ABCC7 p.Arg1158* Complex cystic fibrosis allele R334W-R1158X results in reduced levels of correctly processed mRNA in a pancreatic sufficient patient. Login to comment