title: Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia.
abstract: Renal hypouricemia is an inherited disorder characterized by impaired renal urate (uric acid) reabsorption and subsequent low serum urate levels, with severe complications such as exercise-induced acute renal failure and nephrolithiasis. We previously identified SLC22A12, also known as URAT1, as a causative gene of renal hypouricemia. However, hypouricemic patients without URAT1 mutations, as well as genome-wide association studies between urate and SLC2A9 (also called GLUT9), imply that GLUT9 could be another causative gene of renal hypouricemia. With a large human database, we identified two loss-of-function heterozygous mutations in GLUT9, which occur in the highly conserved "sugar transport proteins signatures 1/2." Both mutations result in loss of positive charges, one of which is reported to be an important membrane topology determinant. The oocyte expression study revealed that both GLUT9 isoforms showed high urate transport activities, whereas the mutated GLUT9 isoforms markedly reduced them. Our findings, together with previous reports on GLUT9 localization, suggest that these GLUT9 mutations cause renal hypouricemia by their decreased urate reabsorption on both sides of the renal proximal tubules. These findings also enable us to propose a physiological model of the renal urate reabsorption in which GLUT9 regulates serum urate levels in humans and can be a promising therapeutic target for gout and related cardiovascular diseases.
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. hmatsuo@ndmc.ac.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.forename: Toshinori
authors.initials: T
authors.lastname: Chiba
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Hideharu
authors.initials: H
authors.lastname: Domoto
authors.forename: Kanokporn
authors.initials: K
authors.lastname: Phetdee
authors.forename: Pattama
authors.initials: P
authors.lastname: Wiriyasermkul
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Oda
authors.forename: Junichiro
authors.initials: J
authors.lastname: Nishiyama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Kamakura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
mesh_terms: D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005091:Exons; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D014527:Uric Acid / Q000097:blood* / Q000378:metabolism*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C411811:SLC2A9 protein, human; D014527:Uric Acid