SLC2A9 – Hereditary Renal Hypouricemia (RHUC2)

Hereditary renal hypouricemia type 2 (RHUC2) is an autosomal recessive disorder characterized by severe hypouricemia, elevated renal fractional excretion of uric acid (FE-UA), exercise-induced acute kidney injury (EIAKI) and nephrolithiasis. Bi-allelic loss-of-function variants in SLC2A9, encoding the facilitative glucose transporter GLUT9, disrupt urate reabsorption in the proximal tubule, leading to clinical complications. The clinical hallmarks include recurrent abdominal pain, fever, nausea and insomnia in the context of profound hypouricemia and high FE-UA.

Multiple independent case reports have identified pathogenic SLC2A9 variants in diverse ethnic groups. A Pakistani man with recurrent EIAKI harbored compound heterozygosity for c.1138C>T (p.Arg380Trp) and c.646G>C (p.Gly216Arg) ([PMID:24397858]). An Austrian family presented with homozygous c.512G>A (p.Arg171His) in two siblings, with heterozygous carriers unaffected, confirming autosomal recessive transmission ([PMID:27116386]). A 43-year-old patient with bilateral loin pain, nausea and sleeplessness carried two heterozygous SLC2A9 mutations, underscoring variable expressivity ([PMID:38129773]).

Larger pedigrees further substantiate the association. In one family, six affected individuals homozygous for p.Leu75Arg exhibited serum uric acid levels of 0.17 ± 0.2 mg/dl and FE-UA >150% ([PMID:19926891]). A second family with a 36-kb deletion resulting in GLUT9 truncation showed four homozygotes with similar biochemical severity. Two additional families carrying R171C and T125M homozygous mutations demonstrated mean serum uric acid of 0.15 ± 0.06 mg/dl and FE-UA 89–150%, without nephrolithiasis or EIAKI ([PMID:21810765]).

Segregation analyses across more than ten affected relatives in multiple pedigrees support recessive inheritance, with heterozygous carriers uniformly asymptomatic and no discordant genotypes reported ([PMID:19926891], [PMID:27116386]).

Functional assays consistently demonstrate loss of GLUT9-mediated urate transport. Xenopus laevis oocyte studies revealed markedly reduced urate flux for p.Arg198Cys and p.Arg380Trp compared to wild-type ([PMID:19026395]). HEK cell overexpression assays and two-electrode voltage clamp studies confirmed decreased transport activity for multiple variants, including p.Gly72Asp, p.N333Ser and p.Met155Val ([PMID:26500098], [PMID:29967582]). Molecular modeling locates many pathogenic residues within the urate conduction channel, predicting structural destabilization and loss of function.

Integration of genetic and experimental data yields a Definitive gene-disease association. Over 30 individuals from more than eight unrelated families carry bi-allelic SLC2A9 variants with concordant phenotype and robust functional validation. No conflicting or refuting evidence has been reported. Key take-home: Bi-allelic SLC2A9 variants definitively cause autosomal recessive RHUC2, guiding genetic diagnosis and management of hypouricemia and exercise-induced renal injury.

References

• American journal of human genetics • 2008 • Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. PMID:19026395
• Journal of the American Society of Nephrology • 2010 • Homozygous SLC2A9 mutations cause severe renal hypouricemia. PMID:19926891
• BMC medical genetics • 2014 • Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9 compound heterozygosity. PMID:24397858
• American journal of nephrology • 2016 • A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia. PMID:27116386
• Nephrology, dialysis, transplantation • 2012 • Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2. PMID:21810765
• BMC nephrology • 2023 • Recurrent exercise-induced acute kidney injury associated with hypouricemia: a case report and literature review. PMID:38129773
• Clinical and experimental nephrology • 2016 • Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. PMID:26500098
• Frontiers in physiology • 2018 • Human Mutations in SLC2A9 (Glut9) Affect Transport Capacity for Urate. PMID:29967582

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