Familial Nephropathy with Gout (FGN) is a rare kidney disorder characterized by reduced fractional excretion of uric acid, precocious and tophaceous gout, and development of chronic renal failure leading to end-stage renal disease. FGN is transmitted as an autosomal dominant trait, clinical fmdings are variable, response to treatment not predictable and the disease pathophysiology is poorly understood. The goals of this proposal are to identify the gene(s) responsible for FGN and to characterize the clinical manifestations of this condition. ? ? We have identified two large families with FGN providing unique opportunities to characterize clinical manifestations and progression of FGN and to identify the gene responsible. Our preliminary studies sublocalize an FGN gene to a 2.0 cM region of chromosome l6p in one family. Linkage data from a second, smaller family is consistent with a broader candidate interval. Additional studies will determine if the same gene is responsible for FGN in both families. The genetic interval we have mapped FGN to is not well characterized. Genetic and physical maps of the region are incomplete and there are no obvious candidate genes for FGN. ? ? We propose an integrated clinical and laboratory approach to identify the gene(s) responsible for FGN. We will longitudinally follow affected family members to better characterize clinical manifestations of FGN (Specific Aim#1). To identify the FGN gene (Specific Aim #2) we propose a hierarchical strategy to 1). Clarify and integrate genetic and physical maps of the candidate interval(s), 2). Continue linkage studies to narrow the candidate interval(s), and 3). Systematically evaluate genes within the interval to identify the gene mutation(s) responsible for FGN in these families. ? ? Identification of the specific gene mutation will provide an important discovery that will (a) elucidate important aspects of uric acid tubular transport, (b) provide an understanding of interstitial kidney disease and chronic renal failure, and (c) help to better define relationships between hyperuricemia, uric acid excretion, and the development of renal failure. Completion of these studies will permit pre-symptomatic diagnosis for individuals with FGN and enhance our ability to evaluate current treatment strategies as well as to develop new, more effective intervention strategies.
