Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

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 Ϯ 0.2 mg/dl, and all had a fractional excretion of uric acid Ͼ150%. 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. 21: 64 -72, 201021: 64 -72, . doi: 10.1681 In most mammals, uric acid (UA) is oxidized by the hepatic enzyme uricase to highly soluble allantoin. In humans, however, this enzyme is inactive as a result of mutational silencing, 1 making UA the end product of purine metabolism. Serum UA concentration depends on both UA production and UA removal by the kidneys and intestinal tract and is high in humans compared with other mammals. Elevation of serum UA levels has been associated with various diseases, including gout, hypertension, and cardiovascular and renal disease. 2 Conversely, it has been suggested that UA has a beneficial role as a natural antioxidant, and low serum UA levels have been linked to several neurologic diseases. 2 Studies of renal handling of UA in humans have J Am Soc Nephrol

Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

“…35 Inactivation of urate/anion transporters eliminate UA absorption and also block secretion of organic anions into the tubular lumen with toxic effects on the renal proximal tubules leading to toxic acute tubular cell injury. 11 In conclusion, RHUC is a rare disorder, but it also needs to be considered in patients coming from areas other than Asia. It is obvious, that for the reliable genotype-phenotype relations, more patients need to be analyzed.…”

“…A defect in the SLC2A9 gene results in more patients with renal failure. URAT1 causing renal hypouricemia B Stiburkova et al AKI in RHUC2 was reported in three homozygous probands 11 and three compound heterozygous 12,14 from a sample of 15 patients and was not described in patients with a heterozygous mutation. These investigations suggest that the frequency of AKI might be different between RHUC1 and heterozygous and homozygous RHUC2.…”

“…9,10 Homozygous and/or compound heterozygous loss-of-function mutations in SLC2A9 responsible for severe hypouricemia, and in most patients complicated by nephrolithiasis and AKI have been described in a variety of ethnic groups: Israeli-Arab, Ashkenazi-Jewish, Japanese, Czech and United Kingdom. [11][12][13][14] The SLC22A12 gene is localized on chromosome 11q13. Ten exons encode two transcript variants of the URAT1 transporter (332 and 553 amino acids), which are specifically expressed on the apical membrane of the proximal tubules in the kidneys and in human vascular smooth muscle cells.…”

Structure of, and functional insight into the GLUT family of membrane transporters

“…Loss of function of GLUT9 results in hypouricemia, presumably as a consequence of both a reduced release of urate from the liver and poor reabsorption from the urine in the kidney. [186][187][188][189][190][191][192] Elevated levels of plasma urate have also been associated with hypertension, gout, and metabolic disease. A number of genome-wide association studies have identif ied polymorphisms in the hSLC2A9 gene.…”

“…However, to date, few, if any, single nucleotide polymorphisms have been demonstrated to have direct effects on the function of the protein when it is expressed in vitro. [187][188][189][190][191][192] It is more likely that such mutations have subtle effects on levels of expression or interactions with other proteins in the cell.…”