SLC22A12 – Hereditary Renal Hypouricemia

SLC22A12 encodes the urate-anion exchanger URAT1, the principal transporter mediating renal tubular reabsorption of uric acid. Biallelic loss-of-function variants in SLC22A12 cause hereditary renal hypouricemia (HRH1; MONDO:0009071), characterized by low serum urate levels and risk of exercise-induced acute kidney injury.

Multiple unrelated AR pedigrees have been reported. A 24-year-old male with homozygous c.774G>A (p.Trp258Ter) presented with recurrent exercise-induced acute kidney injury and familial urolithiasis ([PMID:26848304]). Three Iraqi Jewish families harboring R406C and G444R URAT1 variants showed segregation in all affected members with serum urate 0.5–0.8 mg/dL ([PMID:21148271]). Seven additional presecretory reabsorption defect pedigrees in Japanese and European cohorts identified three truncating and one novel missense variant segregating in 12 affected and 26 relatives ([PMID:15634722]).

The variant spectrum includes truncating alleles (p.Trp258Ter), missense (p.Arg406His, p.Arg406Cys), frameshift (p.Ala51fsTer64), and in-frame deletions. Founder effects are documented for p.Arg406His in Iraqi Jews. Homozygous or compound heterozygous genotypes consistently track with AR inheritance and profound fractional excretion of urate.

Functional assays in Xenopus laevis oocytes demonstrate >70% reduction in urate uptake for p.Trp258Ter, p.Arg406His, p.Gln382Leu, and p.Thr467Met, directly linking URAT1 LOF to HRH1 ([PMID:21148271]; [PMID:15634722]; [PMID:23043931]). Site-directed mutagenesis of conserved K393 in transmembrane domain 8 abolishes >70% urate transport and impairs inhibitor binding, elucidating substrate recognition and highlighting URAT1 as a therapeutic target ([PMID:36188325]).

No studies refute the association; replication over >10 years with extensive segregation and concordant functional data meets ClinGen Definitive criteria.

Key Take-home: Biallelic SLC22A12 variants reliably predict hereditary renal hypouricemia risk and guide diagnostic genotyping and potential URAT1-targeted therapies.

References

• Electrolyte & blood pressure : E & BP • 2015 • A Case Report of Familial Renal Hypouricemia Confirmed by Genotyping of SLC22A12, and a Literature Review. PMID:26848304
• Nephrology, dialysis, transplantation • 2011 • URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. PMID:21148271
• The Journal of clinical endocrinology and metabolism • 2005 • Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. PMID:15634722
• Gene • 2013 • Novel URAT1 mutations caused acute renal failure after exercise in two Chinese families with renal hypouricemia. PMID:23043931
• ACS omega • 2022 • Mutation in Transmembrane Domain 8 of Human Urate Transporter 1 Disrupts Uric Acid Recognition and Transport. PMID:36188325

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