Cystic fibrosis (CF) is a pleiotropic disorder characterized by wide clinical variability. Recent identification of the CF gene has allowed determination of over 100 mutations in the past two years. It is now possible to interpret clinical observations in the context of the precise molecular basis of disease and the consequence to cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo. The focused aim of this research proposal is to examine the effect of specific mutations of the CFTR gene upon the cellular and clinical phenotype of the host. This will require a multi-disciplinary approach. First, the level and character of CFTR transcript and protein expressed in nasal epithelial cells from CF patients will be examined. Second, results will be compared to those obtained from analysis of rectal epithelial cells and when available, other CFTR expressing tissues including pancreas, small intestine, lung, and liver in order to identify and characterize tissue- and genotype-specific variability in mutant CFTR expression. Third, the consequence of specific CF mutations to clinical phenotype (as defined by 14 outcome parameters) will be assessed using multicenter retrospective cohort analysis. Finally, comprehensive mutation analysis of all patients attending the Johns Hopkins Hospital CF center will permit case control studies to assess whether certain mutations cluster at the extremes of the phenotypic spectrum. Assessment of the phenotypic variability among deltaF508 homozygotes and within families with more than one affected child in this CF center may uncover genetic and environmental determinants of outcome controlling for CF genotype. Analysis of the impact of genotype upon cell, tissue, organ system and finally individual will provide valuable information useful for prenatal and prognostic counseling and anticipatory care, may allow discrimination between outcome determinants inherent to CFTR genotype and those caused by genetic modifiers or environment, and may permit tailoring of current and novel therapies to the patients for whom they hold the greatest potential.
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