title: Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion.
abstract: Renal hypouricemia is an inherited and heterogeneous disorder characterized by increased urate clearance (CUA). The authors recently established that urate was reabsorbed via URAT1 on the tubular apical membrane and that mutations in SLC22A12 encoding URAT1 cause renal hypouricemia. This study was undertaken to elucidate and correlate clinical and genetic features of renal hypouricemia. The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and CUA/creatinine clearance (Ccr) to SLC22A12 genotype were examined. Uricosuric (probenecid and benzbromarone) and anti-uricosuric drug (pyrazinamide) loading tests were also performed in some patients. Three patients had exercise-induced acute renal failure (9.4%), and four patients had urolithiasis (12.5%). The authors identified eight new mutations and two previously reported mutations that result in loss of function. Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes. Mutation G774A dominated SLC22A12 mutations (74.1% in 54 alleles). Serum urate levels were significantly lower and CUA/Ccr was significantly higher in heterozygotes compared with healthy subjects; these changes were even more significant in homozygotes and compound heterozygotes. These CUA/Ccr relations demonstrated a gene dosage effect that corresponds with the difference in serum urate levels. In contrast to healthy subjects, the CUA/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid. The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo.
authors.affiliation: Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. ichida@jikei.ac.jp
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.forename: Makoto
authors.initials: M
authors.lastname: Hosoyamada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Miho
authors.initials: M
authors.lastname: Hikita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D007674:Kidney Diseases / Q000235:genetics* / Q000652:urine*; D008297:Male; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins; D010641:Phenotype; D017433:Protein Structure, Secondary; D014527:Uric Acid / Q000652:urine*
chemical_list: D002352:Carrier Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C103862:urate transporter; D014527:Uric Acid