SLC22A12 – Renal Hypouricemia 1

Renal hypouricemia type 1 is an autosomal recessive disorder caused by biallelic loss-of-function variants in SLC22A12, encoding the URAT1 urate transporter. Affected individuals present with defective proximal tubular urate reabsorption leading to severe hypouricemia (serum urate 10%). Clinical complications include exercise-induced acute kidney injury (EIAKI), nephrolithiasis, hematuria, abdominal pain, and vomiting, with full recovery of renal function after conservative management. The disorder shows population-specific recurrent alleles, particularly c.774G>A (p.Trp258Ter) in Japanese cohorts, and manifests with founder effects in Roma and Korean populations.

1 Clinical Validity

Multiple independent studies report over 150 unrelated cases with homozygous or compound heterozygous SLC22A12 variants, including 32 probands in a Japanese multicenter cohort (86% W258X) (PMID:15054642), and 30 additional families in JASN (sum of 32 homozygotes/compound heterozygotes) (PMID:14694169). Segregation in family studies demonstrates recessive inheritance with heterozygous parents unaffected. Functional concordance across cellular assays and oocyte uptake systems confirms pathogenicity.

2 Genetic Evidence

Inheritance is autosomal recessive. Segregation analysis identified one additional affected sibling beyond index case in a consanguineous family with homozygous c.774G>A (p.Trp258Ter) (PMID:14655203). Large case series include over 31 Korean subjects carrying p.Trp258Ter and p.Arg90His, explaining 94% of monogenic cases (PMID:31591475). Variant spectrum comprises at least 15 distinct coding changes: nonsense (p.Trp258Ter), missense (p.Arg90His, p.Thr217Met, p.Thr467Met, p.Ser508Asn), frameshift (c.1289_1290insGG; p.Met430fsTer466), and splice junction variants. Founder alleles such as c.1245_1253del (p.Leu415_Gly417del) are enriched in the Roma population (PMID:27906637).

3 Functional Evidence

In vitro [^14C]urate uptake assays in Xenopus oocytes and HEK293 cells show that URAT1 variants p.Trp258Ter and p.Gln382Leu abolish transport activity, while p.G366R and p.Arg477His display misfolding with ER retention (PMID:15634722). Coexpression with PDZK1 enhances wild-type URAT1 surface expression (Vmax increase 1.4-fold), an effect lost in PDZ-motif mutants (PMID:15304510). Site-directed mutagenesis of key transmembrane residues (K393) confirms the critical role of positive charge for substrate and inhibitor binding, supporting haploinsufficiency as the primary mechanism.

4 Integration & Conclusion

The consistent identification of biallelic loss-of-function SLC22A12 variants in multiple ethnic cohorts, together with robust functional assays demonstrating impaired urate transport and protein mislocalization, supports a Strong gene–disease association. Genetic evidence meets the ClinGen cap with over 100 probands and clear segregation, and functional data reach a Moderate level of evidence. No credible conflicting reports have been described.

Key Take-home: Genetic testing for SLC22A12 variants, particularly c.774G>A (p.Trp258Ter) and c.269G>A (p.Arg90His), enables definitive diagnosis of renal hypouricemia type 1, guiding lifestyle modifications to prevent acute kidney injury and nephrolithiasis.

References

• American Journal of Kidney Diseases • 2003 • Two male siblings with hereditary renal hypouricemia and exercise-induced acute renal failure. PMID:14655203
• Pediatric Nephrology • 2004 • The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia. PMID:15054642
• Journal of the American Society of Nephrology • 2004 • Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. PMID:14694169
• The Journal of Biological Chemistry • 2004 • The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus. PMID:15304510
• 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

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