SLC2A9 – Renal Hypouricemia Type 2

Hereditary renal hypouricemia type 2 (RHUC2) is an autosomal recessive disorder caused by bi‐allelic loss‐of‐function mutations in SLC2A9, encoding the voltage‐sensitive urate transporter GLUT9. Affected individuals exhibit profound hypouricemia, increased fractional excretion of uric acid, nephrolithiasis, and exercise‐induced acute kidney injury. Genetic diagnosis of RHUC2 guides prognostication and management, including hydration strategies to mitigate acute kidney injury risk.

Multiple unrelated families have demonstrated segregation of homozygous or compound heterozygous SLC2A9 variants with disease. A native Austrian family harbored homozygous c.512G>A (p.Arg171His) in two affected siblings, with heterozygous carriers in unaffected relatives (PMID:27116386). In one pedigree, six individuals homozygous for p.Leu75Arg and another with a 36‐kb deletion exhibited serum urate levels 150% (PMID:19926891). Two additional families carried homozygous R171C and T125M mutations, confirming AR inheritance and co‐segregation in four affected members (PMID:21810765).

The variant spectrum includes missense substitutions (p.Arg171His, p.Leu75Arg, p.Thr125Met), frameshift alleles, and large deletions. A recurrent Spanish founder variant c.374C>T (p.Thr125Met) has been documented across multiple RHUC2 kindreds. Functional studies in Xenopus oocytes and mammalian cells consistently show that GLUT9 mutants (p.Arg171Cys, p.Arg198Cys, p.Arg380Trp, p.Thr125Met) have markedly reduced urate transport activity, with normal protein expression but altered topology or channel function (PMID:19026395).

Mechanistically, loss of GLUT9 impairs urate reabsorption on both apical and basolateral membranes of proximal tubular cells, leading to urinary urate wasting and downstream complications. No studies to date have refuted the SLC2A9–RHUC2 association or suggested alternative genetic etiologies for typical RHUC2 phenotypes.

In summary, definitive genetic and functional evidence establishes SLC2A9 as the causative gene for RHUC2. Genetic testing for SLC2A9 variants is clinically useful for diagnosis, family counseling, and management of renal complications in hypouricemic patients.

References

• American journal of nephrology • 2016 • A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia. PMID:27116386
• Journal of the American Society of Nephrology : JASN • 2010 • Homozygous SLC2A9 mutations cause severe renal hypouricemia. PMID:19926891
• Nephrology, dialysis, transplantation • 2012 • Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2. PMID:21810765
• American journal of human genetics • 2008 • Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. PMID:19026395

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