TY - JOUR
T1 - URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews
AU - Dinour, Dganit
AU - Bahn, Andrew
AU - Ganon, Liat
AU - Ron, Rotem
AU - Geifman-Holtzman, Ossie
AU - Knecht, Aaron
AU - Gafter, Uzi
AU - Rachamimov, Ruth
AU - Sela, Ben Ami
AU - Burckhardt, Gerhard
AU - Holtzman, Eliezer J.
N1 - Funding Information:
Index patients and family members were evaluated for clinical history of renal stones, exercise-induced acute renal injury or other renal diseases. Blood and spot urine samples were collected for measurement of UA and creatinine levels and for genetic analysis. The study was approved by the institutional and Ministry of Health review boards for human experimentation. All participants gave written informed consent. Parental consent was obtained for a 17-year-old subject.
PY - 2011/7
Y1 - 2011/7
N2 - 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 0.50.8 mg% and a fractional excretion of uric acid of 5085%. 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.
AB - 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 0.50.8 mg% and a fractional excretion of uric acid of 5085%. 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.
KW - GLUT9
KW - URAT1
KW - hereditary renal hypouricaemia
KW - urate efflux
KW - uric acid
UR - http://www.scopus.com/inward/record.url?scp=79960028752&partnerID=8YFLogxK
U2 - 10.1093/ndt/gfq722
DO - 10.1093/ndt/gfq722
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AN - SCOPUS:79960028752
SN - 0931-0509
VL - 26
SP - 2175
EP - 2181
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 7
ER -