Hereditary Renal Hypouricemia Caused by a Novel SLC2A9 Variant: Functional Characterization and Systematic Literature Review

Congenital renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), type 2 in the SLC2A9 gene (GLUT9). We describe the clinical history, biochemical and molecular genetic findings of a 3-year-old girl with severe hypouricemia (72–84 µmol/L), and an increased fractional excretion of uric acid (21.4–23.6%). Urinary xanthine and hypoxanthine concentrations were within the reference range. Sequencing analyses focusing on genes causing renal hypouricemia identified a new heterozygous variant c.340G > T (p.V114L) in exon 3 of the SLC2A9 gene. No sequence variants in other candidate uric acid transporter were found. Functional in vitro study with 14 C radiolabeled uric acid with HEK293-A cells showed significantly decreased urate uptake in this novel variant. Our findings provide a better pathogenic understanding of renal hypouricemia and the pathophysiological role of the GLUT9 transporter.