Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia
Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia
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DOI：
10.1210/jc.2004-1111
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发表时间：
2005-04-01
影响因子：
5.8
通讯作者：
Kitamura, K
中科院分区：
文献类型：
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作者：
Wakida, N;Tuyen, DG;Kitamura, K
迄今为止，已在特发性肾性低尿酸血症患者中发现了11例人类尿酸转运蛋白1 （hURAT1）基因功能突变缺失。在本研究中，我们研究了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肾性低尿酸血症家族的临床特征和hURAT1基因突变。调查了12名受影响的受试者和26名家庭成员。采用PCR和直接测序法分析突变。通过非洲爪蟾卵母细胞对[C-14]尿酸的摄取来测定野生型和突变型hURAT1的尿酸转运活性。突变分析揭示了三个先前报道的突变（G774A， A1145T和1639-1643 del-GTCCT）和一个新的突变（T1253G）存在于分泌前重吸收缺陷型的家族中。在分泌后重吸收缺陷型中，hURAT1基因编码区没有突变，hURAT1位点也没有明显的分离模式。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），提示T1253G是一种功能缺失突变，hURAT1与分泌前重吸收缺陷型家族性肾性低尿酸血症有关。未来的研究需要确定分泌后再吸收缺陷型家族性肾性低尿酸血症的相关基因。
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 [C-14] 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.