ABCMdb

PMID: 12940920

Rowntree RK, Harris A
The phenotypic consequences of CFTR mutations.
Ann Hum Genet. 2003 Sep;67(Pt 5):471-85., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The majority of the other CFTR mutations are very rare with only four other mutations (G542X, N1303K, G551D and W1282X) having overall frequencies above 1%. Login to comment 47 ABCC7 p.Gly542* These mutations, the most common being G542X, prevent the synthesis of a stable protein or result in the production of a truncated protein due to the creation of a premature termination codon. Login to comment 56 ABCC7 p.Arg553* ABCC7 p.Gly542* Alternatively, recent studies showed that premature stop codons, such as G542X and R553X, were suppressed by the addition of aminoglycoside antibiotics (e.g. gentamicin or G418) that are known to stimulate the suppression of stop codons in various organisms by near-cognate mis-pairing of an aminoacyl-tRNA with the premature stop codon (Howard et al. 1996). Login to comment 70 ABCC7 p.Gly551Asp The missense mutation G551D is an example of a class III mutation. Login to comment 73 ABCC7 p.Arg117His Class IV mutations include cases where the CFTR gene encodes a protein that is correctly trafficked to the cell membrane and responds to stimuli but generates a reduced Cl- current (for example R117H). Login to comment 78 ABCC7 p.Gly622Asp ABCC7 p.Glu822Lys ABCC7 p.Arg792Gly ABCC7 p.Ala800Gly ABCC7 p.His620Gln Three mutant CFTR proteins, G622D, R792G and E822K, that were transiently expressed in COS cells showed lower chloride channel activities when compared to wild-type CFTR, whereas mutants H620Q and A800G showed increased activities. Login to comment 79 ABCC7 p.Glu826Lys ABCC7 p.Thr665Ser Furthermore, mutants T665S and E826K showed no difference from the wild-type channel conductance. Login to comment 80 ABCC7 p.Asp1152His ABCC7 p.Ile1139Val ABCC7 p.Asp1154Gly ABCC7 p.Met1137Val Several mutations within exon 18, which encodes transmembrane helix 12 and the subsequent intracytoplasmic loop, were also shown to fall into Class IV with M1137V, I1139V, M1140, D1152H and D1154G mutants exhibiting significantly reduced cAMP-activated chloride currents (Vankeerberghen et al. 1998b). Login to comment 85 ABCC7 p.Gln1412* The shortest truncation reported that caused CF with pancreatic insufficiency and recurrent pulmonary infection is Q1412X, that lacks 70 amino acids (CF Genetic Analysis Consortium). Login to comment 122 ABCC7 p.Trp1282* Ashkenazi Jews have a low incidence of F508 but have an increased frequency (60%) of the nonsense mutation W1282X (Shoshani et al. 1992). Login to comment 132 ABCC7 p.Asp565Gly Additionally, point mutations that are assumed to be single nucleotide polymorphisms (SNPs) play a role in CF disease by interfering with splicing signals (see aberrant splicing of exon 9) and causing mis-splicing of the gene, such as 1717-9T → C-D565G in exon 12 (Tzetis et al. 2001), as reviewed by Cartegni et al. 2002. Login to comment 155 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Mutations R117H, R334W and R347P are usually associated with less severely impaired pancreatic function (reviewed by Tsui, 1992). Login to comment 170 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Another example of correlation between a CFTR allele and pulmonary disease is the A455E mutation, which was associated with milder lung and pancreatic disease in A455E compound heterozygotes than F508 homozygotes in Quebec (De Braekeleer et al. 1997). Login to comment 172 ABCC7 p.Arg553* ABCC7 p.Arg553Gln The first complex allele to be described was in 1991 where R553Q was detected on the same allele as F508 of a CF patient also carrying the R553X mutation (Dork et al. 1991). Login to comment 173 ABCC7 p.Arg553Gln This patient exhibited pancreatic insufficiency and severe pulmonary disease but a borderline sweat test, suggesting that the R553Q mutation is somehow modulating the severity of CF disease normally associated with F508. Login to comment 174 ABCC7 p.Arg553Gln Analysis of the crystal structure of the related ABC protein, HisP, showed that these two mutations are predicted to lie in adjacent α-helices and that R553Q lies in a region essential for the integrity of protein folding (Hung et al. 1998). Login to comment 176 ABCC7 p.Ser549Arg The promoter mutation -102T → A has been found in association with S549R (T → G) (Romey et al. 1999). Login to comment 177 ABCC7 p.Ser945Leu Two individuals who had genotypes 102T → A + S549R(T → G)/ F508 and 102T → A + S549R(T → G)/S945L both had mild CF disease and were pancreatic sufficient. Login to comment 178 ABCC7 p.Ser549Arg As the S549R mutation has previously been described as a 'severe` allele, associated with pancreatic insufficiency, it appears that cis- mutations can modulate the clinical phenotype. Login to comment 181 ABCC7 p.Arg347His ABCC7 p.Asp979Ala Clain et al. investigated the complex allele with two mild mutations (R347H-D979A) previously identified in pancreatic sufficient CF patients and CBAVD patients respectively (Clain et al. 2001). Login to comment 182 ABCC7 p.Arg347His ABCC7 p.Asp979Ala ABCC7 p.Asp979Ala R347H was found to be associated with moderately defective Cl-channel activity whereas D979A led to misprocessing of CFTR. Login to comment 183 ABCC7 p.Arg347His ABCC7 p.Asp979Ala The double mutant, R347H-D979A, combined both defects and dramatically decreased the Cl- current. Login to comment 184 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Asp443Tyr The complex allele described contained three missense mutations, D443Y, G576A and R668C (Abramowicz et al. 2000). Login to comment 186 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala The complex allele G576A-R668C had been reported in an individual with a normal sweat test, although the affected members of the family exhibited a mild CF phenotype. Login to comment 187 ABCC7 p.Asp443Tyr It is therefore possible that the inclusion of the D443Y mutation resulted in the CF phenotype in these patients. Login to comment 188 ABCC7 p.Arg117His The R117H mutation is usually responsible for mild CF disease due to production of a partially functional protein that is localised to the apical cell membranes. Login to comment 189 ABCC7 p.Arg117His However, this mutation appears to be modulated by the presence of the T7 allele in intron 8 of the CFTR gene, with a CF phenotype only occurring if R117H is present with the T5 allele (Kiesewetter et al. 1993). Login to comment 190 ABCC7 p.Arg117His ABCC7 p.Arg117His In eight individuals with CBAVD and one asymptomatic individual (R117H/ F508) the R117H allele was found in association with the T7 allele. Login to comment 192 ABCC7 p.Arg117His Therefore, R117H/T7 individuals would produce normal levels of partially functional CFTR resulting in a mild CF phenotype. Login to comment 193 ABCC7 p.Arg117His ABCC7 p.Arg117His This is in contrast to R117H/T5 individuals where the amount of full-length CFTR mRNA is reduced, resulting in a more severe phenotype due to a decreased amount of R117H CFTR protein at the cell membrane. Login to comment