A case of renal hypouricemia type 1 associated with compound heterozygous URAT1/SLC22A12 variants A209V and F379L: clinical evidence for their pathogenic significance.

Renal hypouricemia (RHUC) is an inherited renal tubular disorder characterized by low serum uric acid levels and excessive urinary uric acid excretion due to impaired urate reabsorption in proximal tubules. Type 1 RHUC (RHUC1) is caused by pathogenic variants in URAT1/SLC22A12. In Japanese patients, recurrent variants such as W258X and R90H account for a substantial proportion of RHUC1 cases; however, the clinical significance of rare URAT1 variant combinations remains incompletely understood. A 69-year-old woman was referred to our hospital for evaluation of renal dysfunction and hypouricemia. Laboratory examination revealed severe hypouricemia (serum uric acid, 0.7 mg/dL) and markedly increased urinary uric acid excretion (Cua/Ccr, 60.5%). She had chronic kidney disease (CKD) stage G3b and a renal stone. Genetic analysis identified two heterozygous variants, A209V and F379L, in URAT1/SLC22A12 gene. The variants were considered likely to represent compound heterozygosity based on the clinical phenotype and their previously reported functional impairment. Although A209V and F379L have individually been reported to impair urate transport, the clinical phenotype associated with this variant combination has not been well characterized. The severe hypouricemia and excessive urinary uric acid excretion observed in this patient provide clinical evidence supporting the pathogenic significance of the A209V and F379L combination. The coexistence of nephrolithiasis and CKD further raises the possibility that excessive urinary urate excretion and stone formation may contribute to renal dysfunction. In addition, the improvement in stone-related urinary abnormalities during potassium citrate treatment suggests that urinary alkalization may be beneficial in the management of nephrolithiasis associated with RHUC.