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Mutations in Human Urate Transporter 1 Gene in Presecretory Reabsorption Defect Type of Familial Renal Hypouricemia

Departments of Nephrology (N.W., D.G.T., M.A., T.M., H.N., K.T., K.K.) and Biopharmaceutics (N.W., M.O.), Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan; Department of Pediatrics, Sapporo Tokushukai Hospital (T.Ok., O.U.), Hokkaido 003-0021, Japan; Department of Pediatrics, Fujita Health University School of Medicine (M.T.), Aichi 470-1192, Japan; Department of Medicine, Kasukabe Shuwa Hospital (S.K.), Saitama 344-0038, Japan; Department of Medicine, Kitasato Medical Center Hospital (Y.Y., H.S.), Saitama 364-0026, Japan; Second Department of Internal Medicine (T.Od., Y.K.) and First Department of Physiology (H.M.), National Defense Medical College, Saitama 359-0042, Japan; and Department of Pharmacology and Toxicology, Kyorin University School of Medicine (M.H., H.E.), Tokyo 181-8611, Japan

Address all correspondence and requests for reprints to: Dr. Kenichiro Kitamura, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, Kumamoto 860-8556, Japan. E-mail: ken{at}gpo.kumamoto-u.ac.jp.

To date, 11 loss of function mutations in the human urate transporter 1 (hURAT1) gene have been identified in subjects with idiopathic renal hypouricemia. In the present studies we investigated the clinical features and the mutations in the hURAT1 gene in seven families with presecretory reabsorption defect-type renal hypouricemia and in one family with the postsecretory reabsorption defect type. Twelve affected subjects and 26 family members were investigated. Mutations were analyzed by PCR and the direct sequencing method. Urate-transporting activities of wild-type and mutant hURAT1 were determined by [¹⁴C]urate uptake in Xenopus oocytes. Mutational analysis revealed three previously reported mutations (G774A, A1145T, and 1639–1643 del-GTCCT) and a novel mutation (T1253G) in families with the presecretory reabsorption defect type. Neither mutations in the coding region of hURAT1 gene nor significant segregation patterns of the hURAT1 locus were detected in the postsecretory reabsorption defect type. All hURAT1 mutants had significantly reduced urate-transporting activities compared with wild type (P < 0.05; n = 12), suggesting that T1253G is a loss of function mutation, and hURAT1 is responsible for the presecretory reabsorption defect-type familial renal hypouricemia. Future studies are needed to identify a responsible gene for the postsecretory reabsorption defect-type familial renal hypouricemia.

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