ABCMdb

PMID: 10773783

Zielenski J
Genotype and phenotype in cystic fibrosis.
Respiration. 2000;67(2):117-33., [PubMed]

Sentences

No. Mutations Sentence Comment

76 ABCC7 p.Arg117His Type of mutation Mutations that are predicted to prevent CFTR biosynthesis or produce grossly changed, unstable or nonfunctional proteins tend to have severe phenotypic consequences (type: nonsense, frameshift, splice, large in-frame deletion or insertion); effects of mutations that cause minor, local changes in the protein may range from mild to severe depending on other factors such as its molecular mechanism, amino acid change or location (type: missense, small in-frame deletion or insertion) B Molecular mechanism Immediate consequence of the mutation for CFTR biosynthesis, processing, trafficking to the membrane, stability and function (classes of mutations); the mechanisms of mutations are evaluated empirically on the molecular and cellular levels C Position in the gene (protein) Applies particularly to minor, local changes (missense); mutations in structurally or functionally critical regions of the protein tend to correlate with more severe phenotypes when compared with mutations in less important regions; amino acid substitutions in highly conserved regions of CFTR protein may also have more severe phenotypic consequences than mutations from unconserved regions D Net molecular effect The net amount of the functional CFTR present in the apical membrane of secretory epithelial cells, irrespective of type mutation or its mechanism; production of even a small amount of functional CFTR may be sufficient to prevent a severe disease (class IV and V mutations) E Intragenic modulators (complex alleles) In some cases, a second change in the same allele may modulate the phenotypic effect of the primary mutation; for example, the missense mutation R117H associated with the 5T variant in the T-tract of the acceptor splice site of intron 8 is typically associated with the pancreatic sufficient form of CF but only with infertility (males) or asymptomatic presentation (females) when on the 7T background F Impact of second mutation As a recessive disease, CF requires the presence of mutations in each allele; therefore, the type and molecular consequences of the second mutation in the genotype may be critical for the clinical outcome; for example, a severe allele is associated with PI only if the second mutation is severe; conversely, one mild mutation is sufficient to preserve pancreatic function, irrespective of the type of the second allele G Site of expression/organ pathophysiology/ secondary modulation A phenotypic impact of a mutation also depends on where the mutation is expressed and organ-specific pathophysiology; in some organs like the pancreas, a CFTR genotype closely correlates with the severity of its phenotype (PI vs. PS); in lungs, with complex pathophysiology, the primary effect of a particular genotype may be considerably modulated by secondary genetic factors and environment lated form and transported to the apical membrane. Login to comment 87 ABCC7 p.Gly551Asp Alterations within NBD1 (such as missense mutation G551D) may also affect CFTR regulation of other channels such as the outwardly rectifying chloride channel [21] or ROMK2 potassium channel [22]. Login to comment 90 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Several mutations (R117H, R334W, R347P) were shown to affect the properties of CFTR single-channel conductance [23]. Login to comment 94 ABCC7 p.Ala455Glu Various mutations may be associated with reduced biosynthesis of fully active CFTR due to partially aberrant splicing (3849+10kbC→T) [25], promoter mutations or inefficient trafficking (A455E) [26, 27]. Login to comment 99 ABCC7 p.Gln1412* These are usually nonsense or frameshift mutations (Q1412X, 4326delTC, 4279insA) causing a 70to 100-bp truncation of the C-terminus of the CFTR [28] and associated with severe CF presentation. Login to comment 119 ABCC7 p.Gly85Glu Certain missense mutations such as G85E [32] may confer a variable pancreatic phenotype. Login to comment 147 ABCC7 p.Ala455Glu Thus far, the strongest association between mild pulmonary disease and a specific CFTR mutation was found for the missense allele A455E [57, 60, 62]. Login to comment 152 ABCC7 p.Gly551Ser There may be other specific mutations consistently associated with a mild lung presentation, like the G551S allele, but the small number of patients analyzed do not allow for a definite conclusion [55, 58]. Login to comment 165 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Gly542* Both studies showed that certain mild alleles (R117H; A455E; 3849+10kbC→T) from class IV or V tend to be associated with significantly lower Cl sweat levels than those for severe alleles ('F508; 621+1G→T; G542X; R553X, etc.). Login to comment 209 ABCC7 p.Arg117His One of them, R117H, is a missense mutation present both in CF and CBAVD patients. Login to comment 211 ABCC7 p.Arg117His Analysis of T-tract variants co-segregating with this mutation in groups of patients with CF and CBAVD revealed a tendency of the R117H allele to associate with the 5T variant in CF patients and the 7T variant in CBAVD patients. Login to comment 212 ABCC7 p.Arg117His ABCC7 p.Arg117His Thus, the R117H mutation on the 7T background affects almost exclusively the male reproductive tract and is not sufficient to produce other CF symptoms whereas the 5T allele enhances the phenotypic effect of the R117H mutation producing the pancreatic sufficient form of CF (table 1, E). Login to comment 251 ABCC7 p.Ser1455* Sweat Ducts An interesting phenotype, presenting with elevated sweat Cl concentration in the absence of other CF symptoms, has been described in a patient with a nonsense mutation, S1455X. Login to comment 254 ABCC7 p.Ser1455* Detailed analyses of the S1455X CFTR variant have shown that the protein was normally processed and functional and therefore suggests that the truncated stretch of C-terminal amino acids plays some role in the sweat gland. Login to comment