Identification of novel genes causing familial juvenile hyperuricaemic (gouty) nephropathy (FJHN). (360G-Wellcome-094346_Z_10_Z)

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) is an autosomal dominant disorder characterised by reduced excretion of uric acid which leads to gout, renal fibrosis and chronic renal failure. Three genetic causes of FJHN have been defined to date, which are mutations in the UMOD, REN and HNF-1beta genes encoding uromodulin, renin, and hepatocyte nuclear factor-1beta, respectively. However, these UMOD, REN, and HNF-1beta mutations are found in only ~45% of FJHN patients and the rem aining ~55% of patients have mutations in as-yet-unidentified genes. We have mapped two novel FJHN loci to ~5.5Mbp and ~9.1Mbp on chromosomes 2p22.1-p21 and 5p15.33-15.2, respectively. We now propose to identify these genes causing FJHN by using whole exome capture, as the majority of Mendelian inherited disorders are caused by mutations in coding regions of genes. This exome capture will reveal novel non-synonymous variants and we will investigate these further for co-segregation in affected family members, absence in a normal population, evolutionary conservation and likely deleterious effects on the protein. In addition, we will characterise wild-type and mutant gene products by transfecting cultured cells and performing functional assays. These studies will provide important insights into novel mechanisms of FJHN, renal fibrosis and chronic renal failure.