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J Am Soc Nephrol. 2010 Jan;21(1):64-72. doi: 10.1681/ASN.2009040406. Epub 2009 Nov 19.

Homozygous SLC2A9 mutations cause severe renal hypouricemia.

Author information

1
Nephrology and Hypertension Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel. dganit.dinour@sheba.health.gov.il

Abstract

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 +/- 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.

PMID:
19926891
PMCID:
PMC2799278
DOI:
10.1681/ASN.2009040406
[Indexed for MEDLINE]
Free PMC Article

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