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
X
ABCC7 p.Arg117His 10773783:76:1672
status: NEW
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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
X
ABCC7 p.Gly551Asp 10773783:87:51
status: NEW
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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
X
ABCC7 p.Arg117His 10773783:90:19
status: NEW
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ABCC7 p.Arg334Trp
X
ABCC7 p.Arg334Trp 10773783:90:26
status: NEW
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ABCC7 p.Arg347Pro
X
ABCC7 p.Arg347Pro 10773783:90:33
status: NEW
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Several mutations (R117H, R334W, R347P) were shown to affect the properties of CFTR single-channel conductance [23]. Login to comment
94 ABCC7 p.Ala455Glu
X
ABCC7 p.Ala455Glu 10773783:94:193
status: NEW
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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*
X
ABCC7 p.Gln1412* 10773783:99:52
status: NEW
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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
X
ABCC7 p.Gly85Glu 10773783:119:35
status: NEW
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Certain missense mutations such as G85E [32] may confer a variable pancreatic phenotype. Login to comment
147 ABCC7 p.Ala455Glu
X
ABCC7 p.Ala455Glu 10773783:147:130
status: NEW
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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
X
ABCC7 p.Gly551Ser 10773783:152:102
status: NEW
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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
X
ABCC7 p.Arg117His 10773783:165:47
status: NEW
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ABCC7 p.Ala455Glu
X
ABCC7 p.Ala455Glu 10773783:165:54
status: NEW
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ABCC7 p.Arg553*
X
ABCC7 p.Arg553* 10773783:165:226
status: NEW
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ABCC7 p.Gly542*
X
ABCC7 p.Gly542* 10773783:165:219
status: NEW
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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
X
ABCC7 p.Arg117His 10773783:209:13
status: NEW
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One of them, R117H, is a missense mutation present both in CF and CBAVD patients. Login to comment
211 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 10773783:211:130
status: NEW
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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
X
ABCC7 p.Arg117His 10773783:212:10
status: NEW
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ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 10773783:212:212
status: NEW
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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*
X
ABCC7 p.Ser1455* 10773783:251:181
status: NEW
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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*
X
ABCC7 p.Ser1455* 10773783:254:25
status: NEW
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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