Chiba Toshinori, Matsuo Hirotaka, Nagamori Shushi, Nakayama Akiyoshi, Kawamura Yusuke, Shimizu Seiko, Sakiyama Masayuki, Hosoyamada Makoto, Kawai Sayo, Okada Rieko, Hamajima Nobuyuki, Kanai Yoshikatsu, Shinomiya Nariyoshi
a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):261-5. doi: 10.1080/15257770.2013.857781.
Hypouricemia is characterized by low serum uric acid (SUA) levels (≤3.0 mg/dL) with complications such as urolithiasis and exercise-induced acute renal failure. We have previously reported that urate transporter 1 (URAT1/SLC22A12) and glucose transporter 9 (GLUT9/SLC2A9) are causative genes for renal hypouricemia type 1 (RHUC1) and renal hypouricemia type 2 (RHUC2), respectively. In the series of experiments, two families have been revealed to have RHUC2 due to GLUT9 missense mutations R198C or R380W, respectively. Thus far, however, no studies have reported other RHUC2 families or patients with these pathogenic mutations. This study is aimed to find other cases of RHUC2. We performed mutational analyses of GLUT9 exon 6 (for R198C) and exon 10 (for R380W) in 50 Japanese hypouricemia patients. Patients were analyzed out of a collection of more than 2000 samples from the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). We identified a novel male patient with heterogeneous RHUC2 mutation R380W. The SUA of this hypouricemia patient was 2.6 mg/dL, which is similar to that of our previous report (SUA: 2.7 mg/dL). This is the second report indicating RHUC2 patient due to GLUT9 mutation R380W. This mutation occurs in highly conserved amino acid motifs and is reported to be an important membrane topology determinant. R380W is a dysfunctional mutation which completely diminishes the urate transport activities of GLUT9. Our study revealed a second hypouricemia patient with GLUT9 R380W, a pathogenic mutation of RHUC2, which may help to expand our understanding of RHUC pathogenesis.
低尿酸血症的特征是血清尿酸（SUA）水平较低（≤3.0mg/dL），并伴有尿石症和运动诱发的急性肾衰竭等并发症。我们之前曾报道，尿酸转运蛋白1（URAT1/SLC22A12）和葡萄糖转运蛋白9（GLUT9/SLC2A9）分别是1型肾性低尿酸血症（RHUC1）和2型肾性低尿酸血症（RHUC2）的致病基因。在一系列实验中，已发现两个家族分别由于GLUT9错义突变R198C或R380W而患有RHUC2。然而，迄今为止，尚无研究报道其他RHUC2家族或携带这些致病突变的患者。本研究旨在寻找其他RHUC2病例。我们对50名日本低尿酸血症患者的GLUT9外显子6（针对R198C）和外显子10（针对R380W）进行了突变分析。患者是从日本多机构合作队列研究（J-MICC研究）的2000多个样本中挑选出来进行分析的。我们鉴定出一名患有异质性RHUC2突变R380W的新男性患者。该低尿酸血症患者的SUA为2.6mg/dL，与我们之前的报告（SUA：2.7mg/dL）相似。这是第二份表明因GLUT9突变R380W导致RHUC2患者的报告。该突变发生在高度保守的氨基酸基序中，据报道是一个重要的膜拓扑结构决定因素。R380W是一个功能失调的突变，它完全消除了GLUT9的尿酸转运活性。我们的研究发现了第二例患有GLUT9 R380W的低尿酸血症患者，这是RHUC2的一种致病突变，可能有助于扩大我们对RHUC发病机制的理解。
