Identification of a dysfunctional exon-skipping splice variant in GLUT9 / SLC2A9 causal for renal hypouricemia type 2.

Autor:	Toyoda Y; Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan., Cho SK; Molecular Genetics Epidemiology Section, Basic Research Laboratory, National Cancer Institute and Frederick National Laboratory for Cancer Research, Frederick, MD, United States.; Department of Pharmacology, Ajou University School of Medicine, Suwon, South Korea., Tasic V; Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, North Macedonia., Pavelcová K; Institute of Rheumatology, Prague, Czechia., Bohatá J; Institute of Rheumatology, Prague, Czechia., Suzuki H; Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan., David VA; Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan., Yoon J; Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States., Pallaiova A; Nephro Dialysis Center, Michalovce, Slovakia., Šaligová J; Metabolic Clinic, Children's Faculty Hospital, Košice, Slovakia., Nousome D; CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States., Cachau R; Integrated Data Science Section, Research Technologies Branch, National Institute of Allergies and Infectious Diseases, Bethesda, MD, United States., Winkler CA; Molecular Genetics Epidemiology Section, Basic Research Laboratory, National Cancer Institute and Frederick National Laboratory for Cancer Research, Frederick, MD, United States., Takada T; Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan., Stibůrková B; Institute of Rheumatology, Prague, Czechia.; Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czechia.; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2023 Jan 17; Vol. 13, pp. 1048330. Date of Electronic Publication: 2023 Jan 17 (Print Publication: 2022).
DOI:	10.3389/fgene.2022.1048330
Abstrakt:	Renal hypouricemia (RHUC) is a pathological condition characterized by extremely low serum urate and overexcretion of urate in the kidney; this inheritable disorder is classified into type 1 and type 2 based on causative genes encoding physiologically-important urate transporters, URAT1 and GLUT9 , respectively; however, research on RHUC type 2 is still behind type 1. We herein describe a typical familial case of RHUC type 2 found in a Slovak family with severe hypouricemia and hyperuricosuria. Via clinico-genetic analyses including whole exome sequencing and in vitro functional assays, we identified an intronic GLUT9 variant, c.1419+1G>A, as the causal mutation that could lead the expression of p.Gly431GlufsTer28, a functionally-null variant resulting from exon 11 skipping. The causal relationship was also confirmed in another unrelated Macedonian family with mild hypouricemia. Accordingly, non-coding regions should be also kept in mind during genetic diagnosis for hypouricemia. Our findings provide a better pathogenic understanding of RHUC and pathophysiological importance of GLUT9. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Toyoda, Cho, Tasic, Pavelcová, Bohatá, Suzuki, David, Yoon, Pallaiova, Šaligová, Nousome, Cachau, Winkler, Takada and Stibůrková.)
Databáze:	MEDLINE
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