Homozygous SLC2A9 mutations cause severe renal hypouricemia.
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.
Dinour
Dganit
D
Nephrology and Hypertension Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel. dganit.dinour@sheba.health.gov.il
Gray
Nicola K
NK
Campbell
Susan
S
Shu
Xinhua
X
Sawyer
Lindsay
L
Richardson
William
W
Rechavi
Gideon
G
Amariglio
Ninette
N
Ganon
Liat
L
Sela
Ben-Ami
BA
Bahat
Hilla
H
Goldman
Michael
M
Weissgarten
Joshua
J
Millar
Michael R
MR
Wright
Alan F
AF
Holtzman
Eliezer J
EJ
D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D015444:Exercise; D005260:Female; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D053040:Nephrolithiasis / Q000097:blood / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D014527:Uric Acid / Q000097:blood*; D014981:Xenopus; D055815:Young Adult
D051246:Glucose Transport Proteins, Facilitative; C411811:SLC2A9 protein, human; D014527:Uric Acid