ABCMdb

PMID: 15868140

Moskowitz SM, Gibson RL, Effmann EL
Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment.
Pediatr Radiol. 2005 Aug;35(8):739-57. Epub 2005 May 3., [PubMed]

Sentences

No. Mutations Sentence Comment

48 ABCC7 p.Gly542* Class 1 alleles (second panel), such as one with a nonsense mutation in codon 542 that normally encodes glycine (G542X allele), contain premature stop codons that result in truncated RNA messages. Login to comment 50 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Class 3 alleles (fourth panel) encode proteins that reach the cell surface, but contain missense mutations that render them incapable of being activated; replacement of glycine by aspartic acid at codon 551 (G551D allele) exemplifies this class. Login to comment 51 ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro Class 4 alleles (fifth panel) reach the surface and can be activated but with decreased channel conductance and possibly also abnormal regulation of other membrane channels; they are exemplified by replacement of arginine by proline at codon 347 (R347P allele). Login to comment 65 ABCC7 p.Arg117His ABCC7 p.Arg117His For example, substitution of histidine for arginine at codon 117 (R117H) is a class 4 allele that is associated with variable length of a polythymidine tract at the intron 8 splice acceptor. Login to comment 66 ABCC7 p.Arg117His When the R117H allele contains five thymidines at the intron 8 splice acceptor (the ''5T`` form of the acceptor site), it is associated with pancreatic-sufficient CF, whereas when it contains seven thymidines (7T), it is associated with much milder ''atypical`` CF lung disease or only CAVD [18-20]. Login to comment 70 ABCC7 p.Arg117His That the allele frequencies of R117H (7T) and wild type (5T) in the non-CF population approach or exceed the frequencies of these alleles in CF patients [24, 25] reflects the low rate of genetic penetrance of these alleles with respect to CF lung disease and indicates that some pedigrees with atypical forms of CFTR deficiency can exhibit non-Mendelian inheritance patterns. Login to comment 71 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Gly542* Modifier genes as modulators of CF lung phenotype Some DF508 homozygous individuals develop severe obstructive lung disease during the first and second decades of life despite maximal medical therapy, while others with the same genotype have little or no obstructive lung disease despite minimal therapy during Table 2 Examples of disease-associated CFTR alleles CFTR allele Allele class Usual clinical status (when compounded with a severe CFTR allelea ) Allele frequency in Caucasiansb General populationc CF CAVD G542X (9T) 1 Pancreatic-insufficient CF 0.001 0.023 0.003 DF508 (9T) 2 Pancreatic-insufficient CF 0.012-0.016 0.694 0.20 G551D (7T) 3 Pancreatic-insufficient CF 0.001 0.022 0.01 R117H (5T) 4 Pancreatic-sufficient CF 0.0001 0.004 ND R117H (7T) 4 CAVD or carrier 0.002-0.003 0.003 0.04 A455E (9T) 5 Pancreatic-sufficient CF ND 0.001 ND 3849+10kbC fi T 5 Pancreatic-sufficient CF ND 0.007 ND WT (5T) 5 CAVD or carrier 0.042 d 0.19 Other allelese 1-5 Variable 0.002-0.006 0.247 0.55 WT (7T or 9T) Wild-type Carrier 0.935 e e a Severe CFTR allele is defined as a class 1, 2, or 3 allele. Login to comment 89 ABCC7 p.Gly542* This suppression of translational termination might be of therapeutic benefit for genetic disease caused by nonsense mutations such as the CFTR Class 1 allele G542X [36-38]. Login to comment