Identification of a hypouricemia patient with SLC2A9 R380W, a pathogenic mutation for renal hypouricemia type 2

Hypouricemia is characterized by low serum uric acid (SUA) levels (≤3.0 mg/dL) with complications such as urolithiasis and exercise-induced acute renal failure. We have previously reported that urate transporter 1 (URAT1/SLC22A12) and glucose transporter 9 (GLUT9/SLC2A9) are causative genes for renal hypouricemia type 1 (RHUC1) and renal hypouricemia type 2 (RHUC2), respectively. In the series of experiments, two families have been revealed to have RHUC2 due to GLUT9 missense mutations R198C or R380W, respectively. Thus far, however, no studies have reported other RHUC2 families or patients with these pathogenic mutations. This study is aimed to find other cases of RHUC2. We performed mutational analyses of GLUT9 exon 6 (for R198C) and exon 10 (for R380W) in 50 Japanese hypouricemia patients. Patients were analyzed out of a collection of more than 2000 samples from the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). We identified a novel male patient with heterogeneous RHUC2 mutation R380W. The SUA of this hypouricemia patient was 2.6 mg/dL, which is similar to that of our previous report (SUA: 2.7 mg/dL). This is the second report indicating RHUC2 patient due to GLUT9 mutation R380W. This mutation occurs in highly conserved amino acid motifs and is reported to be an important membrane topology determinant. R380W is a dysfunctional mutation which completely diminishes the urate transport activities of GLUT9. Our study revealed a second hypouricemia patient with GLUT9 R380W, a pathogenic mutation of RHUC2, which may help to expand our understanding of RHUC pathogenesis.