ADPKD is a common autosomal dominant disorder with both renal and extrarenal involvement. The gene for ADPKD1, whose mutations comprise about 90% of all clinical cases of ADPKD has been identified and completely cloned and sequenced. The gene for ADPKD2 has been recently localized to chromosome 4q. These discoveries provide an unprecedented opportunity to critically examine the sources of variation of the ADPKD1 clinical phenotype. It is well recognized that there is considerable variation in the clinical expression of ADPKD in both the renal and extrarenal components. Although some of this variation is due to existence of two different responsible loci, the source(s) of a significant component of clinical variation of ADPKD remains yet undefined. The first objective of this proposal is to identify and characterize athe mutations at the ADPKD1 locus and to use that information to test the hypothesis that different mutations (or mutations in different gene domains) are a major cause of clinical differences between families. The hypothesis that anticipation is cause of increased severity in succeeding generations will also be tested. The interaction of other genes with ADPKD1 will also be examined. We hypothesize that genotypic variability at the ADPKD2 and the ADPKD loci (on chromosome 6) is responsible for clinical variation in the ADPKD1 phenotype. These hypotheses will be tested by using affected sib-pair analysis, by comparing families with extreme phenotypes (both very mild and very severe), and by examining very early onset children and their parents. This research represents the first organized effort to study the source of clinical variability in ADPKD1 and takes advantage of the large and unique clinical resource. A better understanding of the mechanisms by which the expression of the ADPKD1 gene is modulated will surely lead to new concepts for more effective treatment of this common disorder.
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