Kawamura Y, Matsuo H, Chiba T, Nagamori S, Nakayama A, Inoue H, Utsumi Y, Oda T, Nishiyama J, Kanai Y, Shinomiya N
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1105-11. doi: 10.1080/15257770.2011.623685.
Renal hypouricemia (MIM 220150) is an inherited disorder characterized by low serum uric acid levels and has severe complications such as exercise-induced acute renal failure and urolithiasis. We have previously reported that URAT1/SLC22A12 encodes a renal urate-anion exchanger and that its mutations cause renal hypouricemia type 1 (RHUC1). With the large health-examination database of the Japan Maritime Self-Defense Force, we found two missense mutations (R198C and R380W) of GLUT9/SLC2A9 in hypouricemia patients. R198C and R380W occur in highly conserved amino acid motifs in the "sugar transport proteins signatures" that are observed in GLUT family transporters. The corresponding mutations in GLUT1 (R153C and R333W) are known to cause GLUT1 deficiency syndrome because arginine residues in this motif are reportedly important as the determinants of the membrane topology of human GLUT1. Therefore, on the basis of membrane topology, the same may be true of GLUT9. GLUT9 mutants showed markedly reduced urate transport in oocyte expression studies, which would be the result of the loss of positive charges in those conserved amino acid motifs. Together with previous reports on GLUT9 localization, our findings suggest that these GLUT9 mutations cause renal hypouricemia type 2 (RHUC2) by their decreased urate reabsorption on both sides of the renal proximal tubule cells. However, a previously reported GLUT9 mutation, P412R, was unlikely to be pathogenic. These findings also enable us to propose a physiological model of the renal urate reabsorption via GLUT9 and URAT1 and can lead to a promising therapeutic target for gout and related cardiovascular diseases.
肾性低尿酸血症（MIM 220150）是一种遗传性疾病，其特征是血清尿酸水平低，并伴有运动诱发的急性肾衰竭和尿路结石等严重并发症。我们之前曾报道，URAT1/SLC22A12编码一种肾尿酸-阴离子交换器，其突变会导致1型肾性低尿酸血症（RHUC1）。通过日本海上自卫队的大型健康检查数据库，我们在低尿酸血症患者中发现了GLUT9/SLC2A9的两个错义突变（R198C和R380W）。R198C和R380W发生在GLUT家族转运体中“糖转运蛋白特征”高度保守的氨基酸基序中。已知GLUT1中的相应突变（R153C和R333W）会导致GLUT1缺乏综合征，因为据报道该基序中的精氨酸残基作为人类GLUT1膜拓扑结构的决定因素很重要。因此，基于膜拓扑结构，GLUT9可能也是如此。在卵母细胞表达研究中，GLUT9突变体显示尿酸转运明显减少，这可能是这些保守氨基酸基序中正电荷丢失的结果。结合之前关于GLUT9定位的报道，我们的研究结果表明，这些GLUT9突变通过降低肾近端小管细胞两侧的尿酸重吸收导致2型肾性低尿酸血症（RHUC2）。然而，先前报道的GLUT9突变P412R不太可能具有致病性。这些发现还使我们能够提出通过GLUT9和URAT1进行肾尿酸重吸收的生理模型，并可能为痛风和相关心血管疾病带来有前景的治疗靶点。
