GENETIC STUDIES OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although much has been learned in the last decade about both the genetics of ADPKD and the phenotypic manifestations of the disease, there is very little information regarding the relationship between genotype and phenotype between or within ADPKD families. Both ADPKD genes, ADPKD1 on chromosome 16 and ADPKD2 on chromosome 4 have been cloned, the protein structures deduced, and numerous mutations in both genes identified. Many studies have reported extreme variation in the expression of ADPKD mutations within and between families. The purpose of this study is to determine the extent to which different genetic factors contribute to this variation, and then to identify the genes or DNA sequences that are involved. We have elucidated many of the extra renal manifestations of the disease including hepatic cystic disease, cardiac valve abnormalities, intracranial aneurysms and others. The phenotypes demonstrate substantial inter- and intra-familial variability, indicating other genes are important in determining specific clinical characteristics. There is clear evidence that locus heterogeneity is a major source of clinical variation in that PKD2 is a much milder form of the disease than PKD1. There is little or no evidence for a relationship between the specific PKD mutation and clinical expression. The overall goal of the genetics project is to couple our uniquely large and well-studied population of autosomal dominant polycystic kidney disease (ADPKD) families with the recent genetic breakthroughs to bring about substantial advances in our understanding of this disease. We expect to study 500 families by the end of the 5-year project period which includes 2000 individuals from all ethnic groups. Genetic testing will be done on participants in one of the three following groups: unaffected at-risk relatives, affected family members and unaffected relatives in ADPKD families. Known affected participants will be asked to consent to blood sampling for genetic testing and kidney function. We will analyze the data collected for effects of the wild-type gene, and the genome screen for gene modifiers. From the substantial advances in our understanding of ADPKD which is the goal of this study, clinical treatment advances and improvements will follow.