ABCMdb

PMID: 12531100

McAuley DF, Elborn JS
Cystic fibrosis: basic science.
Paediatr Respir Rev. 2000 Jun;1(2):93-100., [PubMed]

Sentences

No. Mutations Sentence Comment

23 ABCC7 p.Gly551Asp ABCC7 p.Gly542* After the ࢞F508 mutation, substitution mutations such as G542X (2.4%) and G551D (1.8%) are the next most common mutations.2 Patients who are homozygous for the ࢞F508 gene generally have lung disease, pancreatic insufficiency, obstructive azoospermia, and universally have elevated sweat chlorides. Login to comment 26 ABCC7 p.Arg117His The most common of these is the R117H mutation, which is associated with mild disease and late diagnosis.2 Mutations can be divided into five classes, as illustrated in Figure 1.2 Class 1 and class 2 mutations result in no CFTR trafficking to the cell membrane. Login to comment 28 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Some of these mutations (e.g. class 3 mutation G551D and class 4 mutation R117H) have residual chloride channel activity. Login to comment 37 ABCC7 p.Arg117His ABCC7 p.Arg117His These splicing mutations may occur on the same allele (for example, ࢞F508/R117H (5T)) and be associated with the cystic fibrosis phenotype or on the opposite allele (R117H/IVS8-5T or IVS8-5T/IVS8-5T), resulting in congenital bilateral absence of the vas deferens (CBAVD). Login to comment 38 ABCC7 p.Gly551Asp The presence of 7T or 9T variants alone 94 D. F. MCAULEY AND J. S. ELBORN Table 1 Nomenclature of selected CF mutations (modified from Ferguson-Smith & Connor1 ) Mutation Nomenclature Consequence Class Phenotype 3 Base pair deletion at ࢞F508 In frame deletion for II Severe nucleotides 1652-55 phenylalanine at AA508 G > A Substitution at G551D Missense mutation. Login to comment 39 ABCC7 p.Arg117His III Severe nucleotide 1784 Substitution of aspartic acid for glycine at AA551 R > H Substitution on exon 4 R117H Missence mutation at IV Mild (5T) AA117 Variable (7T) Insertion of aT after 3905 insT Frame shift due to one II Severe nucleotide 3905 base insertion G to A at nucleotide 5 from 5' 2789 + 5G > A Splice junction mutation V Mild junction of intron starting after nucleotide 2789 Splicing mutation of intron 8 IVS8-5T Frequent out-splicing of V Variable exon 9 AA = amino acid; G = glycine;A = alinine; R = Arginine; H = histidine;T = thymidine; IVS = intravening sequence; > = substitution; Ins = insertion. Login to comment 43 ABCC7 p.Arg117His Defective Processing Gogli E.R. R Domain Figure 1 Classification of cystic fibrosis mutations (taken from Knowles et al.2 ) does not cause disease, but R117H with 7T on the same allele has been associated with mild CF disease and CBAVD. Login to comment 48 ABCC7 p.Arg117His Approximately 50% of males with CBAVD have two disease-associated mutations of the CF gene.3 The majority of affected individuals have either the 5T splicing mutation (IVS8-5T) or R117H alleles. Login to comment 52 ABCC7 p.Arg117His ABCC7 p.Asn1303Lys In one study, 10% of patients with CBAVD had mild CF-associated symptoms, but it is possible over time that more may develop lung disease.3 Idiopathic chronic pancreatitis Idiopathic chronic pancreatitis, particularly in the absence of a chronic alcohol history, is associated with mutations of the CF gene.4 ࢞F508, R117H, N1303K and IVS8-5T splicing mutation have all been associated with chronic pancreatitis. Login to comment 54 ABCC7 p.Arg117His The most common combination is a severe mutation such as ࢞F508 associated with a splicing mutation such as IVS8-5T, or a mild mutation such as R117H. Login to comment 59 ABCC7 p.Arg117His The situation for patients with obstructive azoospermia is clear, and mutations of the CF gene, particularly R117H and IVS8-5T, should be sought, a clinical assessment undertaken and appropriate investigations arranged.6 Genes which modify the CF phenotype There have been some interesting studies investigating the possible effect of other gene mutations and polymorphisms on the CF phenotype. Login to comment