PHENOTYPE AND GENOTYPE ANALYSIS

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The cloning of the cystic fibrosis conductance regulator (CFTR) gene has offered a unique opportunity to elucidate the basic defect of cystic fibrosis (CF) whereby rational therapies can be devised. Expression studies show that CFTR functions as a cAMP-regulated chloride channel and the major CF mutation, which accounts for 70% of mutant chromosomes, blocks the biosynthesis of the protein in a processing step. A worldwide consortium has been established to define all the CFTR mutations by systematic analysis of CF patients and, thus far, identified over 400 additional mutations of different types, distributed over the entire coding region of the CFTR gene. While this large number of mutations holds a wealth of information about the structure and function of the CFTR protein, further studies are required to elucidate the consequence of the different mutations. Previous genotype-phenotype correlation studies performed by the applicants have revealed an association of particular classes of mutations with pancreatic sufficiency, a mild form of pancreatic disease. Those studies have in turn provided a functional basis for further molecular characterization of CFTR. These investigators now propose to extend their study to examine a broader spectrum of patients who may have different kinds of mutations in the CFTR gene. In addition to atypical CF patients, they will recruit infertile males with absence of vas deferens and children and young adults with acute, recurrent pancreatitis. The studies are designed to test the hypothesis that phenotypic differences in disease expression between patients with clinical conditions caused by mutations in the CFTR gene are, in part, due to different functional classes of CFTR mutations; different genotypes at the CFTR locus will, in turn, have a specific effect on the severity of the anionic conductance defect of affected epithelial. The specific aims of this application are (1) to continue to determine the genotypes by identifying CFTR mutations in groups of patients with typical manifestations of CF; (2) to recruit and characterize patient groups with atypical manifestations of CF; (3) to define the range and severity of phenotypes in different genotype classes; and (4) to correlate CFTR mutations (or classes of mutations) with the various phenotypes. The information derived from these studies will be essential for understanding the variability of disease manifestations and for the development of suitable approaches to disease diagnosis, pre-symptomatic testing, disease prognosis and treatment.