Renal cysts contribute to the morbidity of 3 autosomal dominant genetic diseases: tuberous sclerosis (TSC), von Hippel Lindau disease (VHL) and autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common hereditary disorders in humans, accounting for 8 to 10% of the cases of end-stage renal disease in the United States, for which medical care costs exceed $200 million a year. TSC affects about 1 in 5,000 live births in the United States. Although TSC has many manifestations including mental retardation, the leading cause of death is renal failure. VHL affects about l in 36,000 Americans. It is of particular interest because the cysts in VHL can progress to renal cell carcinoma. Renal cell carcinoma causes 10,000 deaths annually in the United States. Loss of heterozygosity (LOH) analyses are consistent with a tumor suppressor function for the TSC and VHL genes. The normal role of tumor suppressor genes is to constrain cell growth. LOH refers to deletion of a specific chromosomal region in a benign or malignant tumor. LOH is detected by comparing normal DNA with tumor DNA using polymorphic markers. When LOH is consistently detected in tumors from a patient with a familial tumor syndrome, it suggests that loss of function mutations in a gene within that chromosomal region contribute to the pathogenesis of the tumors. LOH in the chromosomal regions of the TSC and VHL genes has been found in both benign and malignant tumors from TSC and VHL patients. The function the PKD1 gene, which causes ADPKD, is not known. Preliminary results showing loss of heterozygosity in the PKD l region of chromosome 16p 13 in cyst epithelial cells from a patient with ADPKD suggest that PKD1 inactivating mutations contribute to renal cyst pathogenesis. The goal of this project is to find common disease mechanisms leading to renal cysts in these 3 diseases, with the hope that understanding the cause of cysts will lead to therapies that prevent end-stage renal failure in ADPKD and TSC, and renal cell carcinoma in VHL.
The specific aims of this project are 1) to evaluate renal cysts from patients with ADPKD, VHL and TSC for clonality and loss of heterozygosity, to provide evidence that renal cysts are clonal lesions which fit the Knudson tumor suppressor model; 2) to study the pattern of mRNA and protein expression of TSC2 and VHL in normal kidney and in cysts, to understand where these proteins are found in the tubular epithelial cells and elsewhere in the kidney (sequence analysis suggests that both may be in the membrane) and how they might contribute to normal tubular cell function and cyst pathogenesis; and 3) to study the Eker rat model of TSC, to evaluate these cysts for loss of heterozygosity and to study the effect of DNA hypomethylation on renal cyst development.
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