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.

Cancer and Developmental Biology Laboratory Center for Cancer Research National Cancer Institute Frederick MD United States

CCR Collaborative Bioinformatics Resource Center for Cancer Research National Cancer Institute Frederick MD United States

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

Department of Pharmacology Ajou University School of Medicine Suwon South Korea

Department of Pharmacy The University of Tokyo Hospital Tokyo Japan

Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czechia

Faculty of Medicine University Ss Cyril and Methodius Skopje North Macedonia

Institute of Rheumatology Prague Czechia

Integrated Data Science Section Research Technologies Branch National Institute of Allergies and Infectious Diseases Bethesda MD United States

Metabolic Clinic Children's Faculty Hospital Košice Slovakia

Molecular Genetics Epidemiology Section Basic Research Laboratory National Cancer Institute and Frederick National Laboratory for Cancer Research Frederick MD United States

Nephro Dialysis Center Michalovce Slovakia

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