The inherited polycystic kidney diseases now comprise at least four different disease entities. Three of these are autosomal dominant in pattern of inheritance (ADPKD) and two of these have been mapped to chromosome 16 and 4 respectively. The third form remains unmapped. An autosomal recessive form of the disease (ARPKD) has been mapped to chromosome 6. Finally, in addition to the autosomal dominant polycystic kidney diseases, there is an autosomal dominant polycystic liver disease (ADPLD) which is genetically and clinically distinct from polycystic kidney disease, but in which the pattern of liver involvement is indistinguishable from that seen in the polycystic kidney diseases. The gene for PKD1 on chromosome 16 has been cloned and the gene for PKD2 on chromosome 4 is being cloned in the PIs laboratory. These two genetic loci account for about 99% of autosomal dominant polycystic kidney disease occurring world wide. As a direct consequence of the cloning of these genes, several things will become possible. Among these are direct gene based testing for mutations in affected individuals, and as a corollary of that, an analysis of these mutations in terms of the phenotypic expression seen in affected individuals. In the current study, we plan to use the molecular characterizations of individuals affected with any of the cloned forms of polycystic disease (i.e. those forms for which the genes have been identified) in conjunction with well described clinical characterization of patients as a means of better understanding how specific mutations result in specific clinical manifestations. In the United States there are only one or two substantial collections of PKD patients available for such studies. The most complete collection is comprised primarily of Caucasian population and is apparently over-representative of the PKD1 disease genotype. Our goal is to collect a more ethnically diverse group of PKD patients and in addition to collect a more representative distribution of both PKD1 and PKD2, as well as non-PKD1/non-PKD2 forms of the disease. We will study these families clinically using abdominal ultrasonography, echocardiography and magnetic resonance angiography. Molecular genetic characterizations will be used to identify the mutations in the known genes and/or the genetic loci of the disease gene if they are not in PKD1 or PKD2 in these individuals. Data amassed from these studies will allow us to make prognostic determinations based on genotypes about potential outcomes that will help patients and physicians manage their disease better. In addition, we will begin to understand how different genetic loci and/or other factors influence the progression of the disease and this may enable us to identify a target population who are at high risk for developing renal failure in the course of their disease, and in whom more aggressive intervention may be necessary.
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