Mutations in Human Urate Transporter 1 Gene in Presecretory Reabsorption Defect Type of Familial Renal Hypouricemia

Abstract

To date, 11 loss of function mutations in the human urate transporter 1 (hURAT1) gene have been identified in subjects with idiopathic renal hypouricemia. In the present studies we investigated the clinical features and the mutations in the hURAT1 gene in seven families with presecretory reabsorption defect-type renal hypouricemia and in one family with the postsecretory reabsorption defect type. Twelve affected subjects and 26 family members were investigated. Mutations were analyzed by PCR and the direct sequencing method. Urate-transporting activities of wild-type and mutant hURAT1 were determined by [14C]urate uptake in Xenopus oocytes. Mutational analysis revealed three previously reported mutations (G774A, A1145T, and 1639-1643 del-GTCCT) and a novel mutation (T1253G) in families with the presecretory reabsorption defect type. Neither mutations in the coding region of hURAT1 gene nor significant segregation patterns of the hURAT1 locus were detected in the postsecretory reabsorption defect type. All hURAT1 mutants had significantly reduced urate-transporting activities compared with wild type (P < 0.05; n = 12), suggesting that T1253G is a loss of function mutation, and hURAT1 is responsible for the presecretory reabsorption defect-type familial renal hypouricemia. Future studies are needed to identify a responsible gene for the postsecretory reabsorption defect-type familial renal hypouricemia.

Human Renal Organic Anion Transporter 4 Operates as an Asymmetric Urate Transporter

“…hURAT1 possesses an intermediate affinity for urate of K m ϭ 371 M and is held to be responsible for 50% of renal urate reabsorption (11,33). This assumption is supported by the fact that mutations in the hURAT1 gene substantially elevate FE urate up to 60% and lead to the clinical manifestation of idiopathic hypouricemia (11,34). It is interesting that according to the recently postulated four-component model of urate handling in the kidneys (33,35) and that patients without any mutations in the hURAT1 gene show hypouricemia, other apical urate transporters were postulated (36), one of which might be hOAT4.…”

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

“…10,18,24 Oocyte solubilization was done in 500 ml of 0.0625 N NaOH and final suspension was mixed with 3 ml of ULTIMA GOLD (PerkinElmer, Inc., Waltham, MA, USA) for radioactivity determination using a scintillation counter (LSC-5100; ALOKA, Tokyo, Japan). Eight oocytes were used per experiment with tests repeated three times.…”

“…Twenty-five mutations are disease causing. 3,[5][6][7][8][15][16][17][18][19] Five URAT1 variants have been described with a gout phenotype, 20 one variant is associated with increased FE-UA and two variants are associated with reduced FE-UA. 21,22 In this article we present clinical, biochemical, molecular genetics and functional characterization of previously reported p.R477H (CM042475 SNP, source HGMD-PUBLIC 2012.1) and novel p.G366R, p.L415_G417del and p.T467M variants in SLC22A12 gene responsible for RHUC1 in three Czech families.…”

Organic Anion Transporters and Their Implications in Pharmacotherapy

“…After the cloning and characterization of the OAT family members, various SNPs began to be identified in many different populations, including whites, sub-Saharan Africans, Mexican Americans, and Japanese. Table 5 provides a summary of the nonsynonymous SNPs that have been found to occur in the coding regions of hOAT1, hOAT2, hOAT3, hOAT4, and URAT1 (Nishizato et al, 2003;Ichida et al, 2004;Fujita et al, 2005;Wakida et al, 2005;Xu et al, 2005;Erdman et al, 2006;Graessler et al, 2006;Urban et al, 2006). Owing to the critical role of OATs in drug disposition and elimination, the occurrence of SNPs in the coding region of OAT genes may result in interindividual variability in the bioavailability and excretion of many clinically important drugs.…”