title: Expression of a human NPT1/SLC17A1 missense variant which increases urate export.
abstract: Human sodium-dependent phosphate cotransporter type 1 (NPT1/SLC17A1) is one of the urate transporters in the kidney. Our recent study revealed that a common missense variant, I269T (rs1165196), of NPT1 decreases the risk of renal underexcretion gout. Moreover, we demonstrated that human NPT1 is localized to the apical membrane of the renal proximal tubule, and that I269T is the gain-of-function variant which increases the NPT1-mediated urate export. However, the mechanism by which I269T variant increases the urate export remains to be clarified. Thus, we performed immunostaining and functional analysis of human NPT1 using the Xenopus oocyte expression system. For comparison of human NPT1 expression levels of oocyte membrane between 269I (wild type) and 269T (variant), immunostaining was performed with anti-human NPT1 antibodies. As a result, we showed that NPT1 I269T variant did not change the human NPT1 membrane expression levels, although NPT1 I269T variant increased the urate transport compared with NPT1 wild type. Combined with the previous report that I269T variant did not induce Km changes but increased the Vmax of urate transport in a proteoliposome system, our findings suggest that I269T variant increases NPT1-mediated urate export without increase of NPT1 expression levels on the membrane. Thus, I269T, a common missense variant of NPT1, might have faster conformation changes than NPT1 wild type in terms of the alternating-access model of transporters, and increases renal urate export in humans.
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sakiyama
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: b Osaka University, Graduate School of Medicine, Department of Pharmacology, Division of Biosystem Pharmacology , Suita , Osaka , Japan.
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.affiliation: b Osaka University, Graduate School of Medicine, Department of Pharmacology, Division of Biosystem Pharmacology , Suita , Osaka , Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Ling
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Higashino
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Chiba
authors.affiliation: c Department of Pathophysiology , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan.
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.affiliation: b Osaka University, Graduate School of Medicine, Department of Pharmacology, Division of Biosystem Pharmacology , Suita , Osaka , Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
mesh_terms: D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D056726:Genetic Association Studies; D006801:Humans; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D050609:Sodium-Phosphate Cotransporter Proteins, Type I / Q000235:genetics* / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C493546:SLC17A1 protein, human; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D014527:Uric Acid
keywords: SLC transporters; single nucleotide polymorphism; uric acid