2008 JASN IMPACT FACTOR 7.505	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2009040406v1 21/1/64    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dinour, D. Articles by Holtzman, E. J. PubMed PubMed Citation Articles by Dinour, D. Articles by Holtzman, E. J.

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 F. Wright and Eliezer J. Holtzman^*

*Nephrology and Hypertension Institute,
^¶Cancer Research Laboratory,
**Institute of Hematology, and
Institute of Chemical Pathology, Sheba Medical Center, Tel-Hashomer and the Sackler School of Medicine, and
Departments of Pediatrics and
Nephrology and Hypertension, Assaf Harofeh Medical Center, Zerifin, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine Western General Hospital, Edinburgh, United Kingdom;
^||Institute of Structural and Molecular Biology, School of Biological Sciences, and
School of Clinical Sciences and Community Health, University of Edinburgh, Edinburgh, United Kingdom; and
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom

Correspondence: Dr. Dganit Dinour, Nephrology and Hypertension Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel. Phone: 972-3-5302581; Fax: 972-3-5392582; E-mail: dganit.dinour{at}sheba.health.gov.il

Received for publication April 16, 2009. Accepted for publication September 23, 2009.

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.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673