Wakida Naoki, Tuyen Do Gia, Adachi Masataka, Miyoshi Taku, Nonoguchi Hiroshi, Oka Toshiaki, Ueda Osamu, Tazawa Masahiro, Kurihara Satoshi, Yoneta Yoshitaka, Shimada Hajime, Oda Takashi, Kikuchi Yuichi, Matsuo Hirotaka, Hosoyamada Makoto, Endou Hitoshi, Otagiri Masaki, Tomita Kimio, Kitamura Kenichiro
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, Kumamoto 860-8556, Japan.
J Clin Endocrinol Metab. 2005 Apr;90(4):2169-74. doi: 10.1210/jc.2004-1111. Epub 2005 Jan 5.
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.
迄今为止，在特发性肾性低尿酸血症患者中已鉴定出人类尿酸转运蛋白1（hURAT1）基因的11种功能丧失突变。在本研究中，我们调查了7个分泌前重吸收缺陷型肾性低尿酸血症家族和1个分泌后重吸收缺陷型家族的临床特征及hURAT1基因中的突变情况。对12名受影响的受试者和26名家庭成员进行了调查。通过聚合酶链反应（PCR）和直接测序法分析突变情况。通过非洲爪蟾卵母细胞对[14C]尿酸的摄取来测定野生型和突变型hURAT1的尿酸转运活性。突变分析在分泌前重吸收缺陷型家族中发现了3个先前报道的突变（G774A、A1145T和1639 - 1643del - GTCCT）以及1个新突变（T1253G）。在分泌后重吸收缺陷型家族中未检测到hURAT1基因编码区的突变，也未发现hURAT1基因座的显著分离模式。与野生型相比，所有hURAT1突变体的尿酸转运活性均显著降低（P < 0.05；n = 12），这表明T1253G是一种功能丧失突变，且hURAT1是分泌前重吸收缺陷型家族性肾性低尿酸血症的致病原因。未来需要开展研究以确定分泌后重吸收缺陷型家族性肾性低尿酸血症的致病基因。
