title: URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews.
abstract: BACKGROUND
  Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained.
  
  
  METHODS
  Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found.
  
  
  RESULTS
  A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure.
  
  
  CONCLUSIONS
  The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.
authors.affiliation: Nephrology and Hypertension Institute, Sheba Medical Center, Tel-Hashomer and the Sackler School of Medicine, Tel AvivUniversity, Tel Aviv, Israel. dganit.dinour@sheba.health.gov.il
authors.forename: Dganit
authors.initials: D
authors.lastname: Dinour
authors.forename: Andrew
authors.initials: A
authors.lastname: Bahn
authors.forename: Liat
authors.initials: L
authors.lastname: Ganon
authors.forename: Rotem
authors.initials: R
authors.lastname: Ron
authors.forename: Ossie
authors.initials: O
authors.lastname: Geifman-Holtzman
authors.forename: Aaron
authors.initials: A
authors.lastname: Knecht
authors.forename: Uzi
authors.initials: U
authors.lastname: Gafter
authors.forename: Ruth
authors.initials: R
authors.lastname: Rachamimov
authors.forename: Ben-Ami
authors.initials: BA
authors.lastname: Sela
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Holtzman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005190:Family; D005260:Female; D006720:Homozygote; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010641:Phenotype; D015499:Renal Tubular Transport, Inborn Errors / Q000209:etiology* / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D014545:Urinary Calculi / Q000209:etiology* / Q000473:pathology; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human