UMOD-related familial juvenile hyperuricemic nephropathy : mutation detection rate and mutational spectrum. K. Dahan¹, L. Labriola², M.L Lizon¹, M. Smaers¹, O. Devuyst², Y. Pirson². 1) Human Genetics Unit, UCL Saint-Luc Hosp, Brussels, Belgium; 2) Division of Nephrology, UCL Saint-Luc Hosp, Brussels, Belgium.
   A mutation in the UMOD gene has emerged as the major cause of familial juvenile hyperuricemic nephropathy (FJHN). However, the mutation rate detection as well as the spectrum of mutations remains to be evaluated in a large cohort of families. We report on these findings in 50 families (31 from France, 11 from Belgium, 2 from Italy, 2 from Morocco, 1 from England, 1 from Australia, 1 from Germany and 1 from Netherlands) with FJHN. In all kindreds, at least one affected individual had a history of either progressive renal insufficiency related to a histological or clinical picture of chronic interstitial nephritis or hyperuricemia (serum uric acid level > 6 mg/dl) preceding renal failure or disproportionate to the rate of glomerular filtration. In addition, a history of either gout in childhood or in young adulthood or chronic renal failure (CRF) or both was present in at least one first-degree relative among 6, 17 and 27 of families respectively. Two propositus had preserved renal function (2/50, 4%) at a mean age of 53 (range : 35-71), 19 had CRF (19/50, 38%) at a mean age of 40 (range : 2-72) and 29 had reached end-stage renal failure (ESRF) (29/50, 58%) at a mean age of 43.1 (range : 28-64). Renal imaging available in 23 propositus, all with CRF or ESR, revealed the presence of cysts in 14 of them (19/23, 82%). Twenty-one patients had mutation in UMOD gene (21/50, 42%). Of the 21 changes (19 missense, one in-frame deletion and one splicing mutation), all are unique with the exception of a cysteine substitution (p.C315Y) also seen in 2 unrelated patients. These mutations are distributed throughout the exon 4 (18/21, 86%) and 5 (3/21, 14%). This mutational study shows a mutation detection rate of 42 % in a large cohort of FJHN families and confirms that missense mutation involving the 5 region corresponding to codons 32 to 315 of Tamm Horsfall protein is the major mechanism for UMOD defect (19/21, 90%).