Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Dganit Dinour, Nicola K. Gray, Susan Campbell, Xinhua Shu, Lindsay Sawyer, William Richardson, Gideon Rechavi, Ninette Amariglio, Liat Ganon, Ben-Ami Sela, Hilla Bahat, Michael Goldman, Joshua Weissgarten, Michael R. Millar, Alan Wright, Eliezer J. Holtzman

Research output: Contribution to journalArticlepeer-review

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 SLUM, 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.

Original languageEnglish
Pages (from-to)64-72
Number of pages9
JournalJournal of the American Society of Nephrology
Volume21
Issue number1
Early online date6 Jan 2010
DOIs
Publication statusPublished - 21 Jan 2010

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