Mutation in the SLC2A9 Gene: A New Family with Familial Renal Hypouricemia Type 2.
Ontology highlight
ABSTRACT:
SUBMITTER: Maalouli C
PROVIDER: S-EPMC8486506 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Renal hypouricemia is an inherited disorder characterized by impaired renal urate (uric acid) reabsorption and subsequent low serum urate levels, with severe complications such as exercise-induced acute renal failure and nephrolithiasis. We previously identified SLC22A12, also known as URAT1, as a causative gene of renal hypouricemia. However, hypouricemic patients without URAT1 mutations, as well as genome-wide association studies between urate and SLC2A9 (also called GLUT9), imply that GLUT9 could be another causative gene of renal hypouricemia. With a large human database, we identified two loss-of-function heterozygous mutations in GLUT9, which occur in the highly conserved "sugar transport proteins signatures 1/2." Both mutations result in loss of positive charges, one of which is reported to be an important membrane topology determinant. The oocyte expression study revealed that both GLUT9 isoforms showed high urate transport activities, whereas the mutated GLUT9 isoforms markedly reduced them. Our findings, together with previous reports on GLUT9 localization, suggest that these GLUT9 mutations cause renal hypouricemia by their decreased urate reabsorption on both sides of the renal proximal tubules. These findings also enable us to propose a physiological model of the renal urate reabsorption in which GLUT9 regulates serum urate levels in humans and can be a promising therapeutic target for gout and related cardiovascular diseases.
| S-EPMC2668068 | biostudies-literature
Project description: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.
| S-EPMC2799278 | biostudies-literature
Project description:Renal hypouricemia is a rare genetic disorder. Hypouricemia can present as renal stones or exercise-induced acute renal failure, but most cases are asymptomatic. Our previous study showed that two recessive variants of SLC22A12 (p.Trp258*, pArg90His) were identified in 90% of the hypouricemia patients from two independent cohorts: the Korean genome and epidemiology study (KoGES) and the Korean Cancer Prevention Study (KCPS-II). In this work, we investigate the genetic causes of hypouricemia in the rest of the 10% of unsolved cases. We found a novel non-synonymous mutation of SLC2A9 (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in SLCA9b (p.Met155Val in SLC2A9a) hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using Xenopus oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the SLC2A9 protein expression level. Our results will shed light on a better understanding of SLC2A9-mediated uric acid transport and the development of a uric acid-lowering agent.
| S-EPMC8471325 | biostudies-literature
Project description:BACKGROUND: Familial renal hypouricemia (RHUC) is a hereditary disease characterized by hypouricemia, high renal fractional excretion of uric acid (FE-UA) and can be complicated by acute kidney failure and nephrolithiasis. Loss-of-function mutations in the SLC22A12 gene cause renal hypouricemia type 1 (RHUC1), whereas renal hypouricemia type 2 (RHUC2) is caused by mutations in the SLC2A9 gene. CASE PRESENTATION: We describe a 24-year-old Pakistani man who was admitted twice to our hospital for severe exercise-induced acute renal failure (EIARF), abdominal pain and fever; he had very low serum UA levels (0.2 mg/dl the first time and 0.09 mg/dl the second time) and high FE-UA (200% and 732% respectively), suggestive of RHUC. Mutational analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations in the SLC2A9 gene: p.Arg380Trp, already identified in heterozygosity, and p.Gly216Arg, previously found in homozygosity or compound heterozygosity in some RHUC2 patients. Compared with previously reported patients harbouring these mutations, our proband showed the highest FE-UA levels, suggesting that the combination of p.Arg380Trp and p.Gly216Arg mutations most severely affects the renal handling of UA. CONCLUSIONS: The clinical and molecular findings from this patient and a review of the literature provide new insights into the genotype-phenotype correlation of this disorder, supporting the evidence of an autosomal recessive inheritance pattern for RHUC2. Further investigations into the functional properties of GLUT9, URAT1 and other urate transporters are required to assess their potential research and clinical implications.
| S-EPMC3890613 | biostudies-literature
Project description:BackgroundTo identify potential causative mutations in SLC2A9 and SLC22A12 that lead to hypouricemia or hyperuricemia (HUA).MethodsTargeted resequencing of whole exon regions of SLC2A9 and SLC22A12 was performed in three cohorts of 31 hypouricemia, 288 HUA and 280 normal controls.ResultsA total of 84 high-quality variants were identified in these three cohorts. Eighteen variants were nonsynonymous or in splicing region, and then included in the following association analysis. For common variants, no significant effects on hypouricemia or HUA were identified. For rare variants, six single nucleotide variations (SNVs) p.T21I and p.G13D in SLC2A9, p.W50fs, p.Q382L, p.V547L and p.E458K in SLC22A12, occurred in totally six hypouricemia subjects and were absent in HUA and normal controls. Allelic and genotypic frequency distributions of the six SNVs differed significantly between the hypouricemia and normal controls even after multiple testing correction, and p.G13D in SLC2A9 and p.V547L in SLC22A12 were newly reported. All these mutations had no significant effects on HUA susceptibility, while the gene-based analyses substantiated the significant results on hypouricemia.ConclusionOur study first presents a comprehensive mutation spectrum of hypouricemia in a large Chinese cohort.
| S-EPMC6625124 | biostudies-literature
Project description:BACKGROUND:Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport, reabsorption insufficiency and /or acceleration of secretion. The affected individuals are predisposed to nephrolithiasis and recurrent episodes of exercise-induced acute kidney injury. Type 1 is caused by dysfunctional variants in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). To date, more than 150 patients with the loss-of-function mutations for the SLC22A12 gene have been found (compound heterozygotes and/or homozygotes), most of whom are Japanese and Koreans. CASE PRESENTATION:Herein, we report a nine year old Sri Lankan boy with renal hypouricemia (serum uric acid 97 ?mol/L, fractional excretion of uric acid 33%).The sequencing analysis of SLC22A12 revealed a potentially deleterious missense variant c.1400C?>?T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. CONCLUSIONS:This is the first identification of a family with mild renal hypouricemia1 associated to the p.T467 M variant. Detailed investigations of urate blood and urine concentrations in patients with unexplained hypouricemia are needed and renal hypouricemia should also be considered in patients other than those from Japan and/or Korea. Our finding confirms an uneven geographical and ethnic distribution of Romany prevalent SLC22A12 variant that need to be considered in Asian patients (population data Genome Aggregation Database: allele frequency in South Asia 0.007055, in East Asia 0.001330).
| S-EPMC6025733 | biostudies-literature
Project description:BackgroundRenal hypouricemia (RHUC) is a genetic disorder caused by mutations in the SLC22A12 gene, which encodes the major uric acid (UA) transporter, URAT1. The clinical course of related, living donor-derived RHUC in patients undergoing kidney transplantation is poorly understood. Here, we report a case of kidney transplantation from a living relative who had an SLC22A12 mutation. After the transplantation, the recipient's fractional excretion of UA (FEUA) decreased, and chimeric tubular epithelium was observed.Case presentationA 40-year-old man underwent kidney transplantation. His sister was the kidney donor. Three weeks after the transplantation, he had low serum-UA, 148.7 μmol/L, and elevated FEUA, 20.8% (normal: < 10%). The patient's sister had low serum-UA (101.1 μmol/L) and high FEUA (15.8%) before transplant. Suspecting RHUC, we performed next-generation sequencing on a gene panel containing RHUC-associated genes. A heterozygous missense mutation in the SLC22A12 gene was detected in the donor, but not in the recipient. The recipient's serum-UA level increased from 148.7 μmol/L to 231.9 μmol/L 3 months after transplantation and was 226.0 μmol/L 1 year after transplantation. His FEUA decreased from 20.8 to 11.7% 3 months after transplantation and was 12.4% 1 year after transplantation. Fluorescence in situ hybridization of allograft biopsies performed 3 months and 1 year after transplantation showed the presence of Y chromosomes in the tubular epithelial cells, suggesting the recipient's elevated serum-UA levels were owing to a chimeric tubular epithelium.ConclusionsWe reported on a kidney transplant recipient that developed RHUC owing to his donor possessing a heterozygous mutation in the SLC22A12 (URAT1) gene. Despite this mutation, the clinical course was not problematic. Thus, the presence of donor-recipient chimerism in the tubular epithelium might positively affect the clinical course, at least in the short-term.
| S-EPMC7364597 | biostudies-literature
Project description:Renal hypouricemia (RHUC) is a disease caused by dysfunction of renal urate reabsorption transporters; however, diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC. This review describes a world-first clinical practice guideline (CPG) and its first version in English for this condition. It was developed following the "MINDS Manual for Guideline Development" methodology, which prioritizes evidence-based medicine. It was published in Japanese in 2017 and later translated into English. The primary goal of this CPG is to clarify the criteria for diagnosing RHUC; another aim is to work towards a consensus on clinical decision-making. One of the CPG's unique points is that it contains textbook descriptions at the expert consensus level, in addition to two clinical questions and recommendations derived from a systematic review of the literature. The guidance shown in this CPG makes it easy to diagnose RHUC from simple blood and urine tests. This CPG contains almost all of the clinical foci of RHUC: epidemiology, pathophysiology, diagnostic guidance, clinical examinations, differential diagnosis, and complications, including exercise-induced acute kidney injury and urolithiasis. A CPG summary as well as a clinical algorithm to assist healthcare providers with a quick reference and notes from an athlete for both physicians and patients are included. We hope that this CPG will help healthcare providers and patients to make clinical decisions, and that it will promote further research on RHUC.
| S-EPMC6437292 | biostudies-literature
Project description:Familial renal glucosuria (FRG) is characterized by persistent glucosuria in the presence of normal serum glucose concentrations, while other impairments of tubular function are absent. Mutations in the sodium-glucose co-transporter 2 (SLC5A2) gene have been found to be responsible for FRG. However, direct evidence for the presence of SLC5A2 mutant in renal tissues is very rare. In previous studies, a non-sense mutation (c.1320 G>A:p.W440X) that would cause premature termination of the protein was found. However, the effects in the renal tissues were not reported. In the current study, a patient with FRG and a urinary glucose excretion rate of 8.3 g/day is described, for whom a novel missense mutation (c.1319G>A:p.W440X) was revealed by sequencing. Furthermore, in the immunofluorescence examination of a renal biopsy specimen, SLC5A2 was detected in the apical side of the proximal convoluted tubule, discontinuously decreased in comparison with that in normal and disease controls. The results imply that both wild-type SLC5A2 and mutant SLC5A2 with abnormal distribution were expressed in the renal tissues, and that the reduction of SLC5A2 expression and function were due to the c.1319G>A:p.W440X mutation. The current study provides valuable clues regarding the SLC5A2 molecule from genotype to phenotype in families affected by FRG.
| S-EPMC4950299 | biostudies-literature
Project description:Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury (AKI). Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), type 2 in the SLC2A9 gene (GLUT9). This article describes three Czech families with RHUC type 1. The serum UA in the probands was 0.9, 1.1 and 0.5 mg/dl and expressed as an increase in the fractional excretion of UA (48, 43 and 39%). The sequencing analysis of SLC22A12 revealed three novel variants: p.G366R, p.T467M and a deletion p.L415_G417del. A detailed metabolic investigation in proband C for progressive visual failure supported suspicion of neuronal ceroid lipofuscinosis type 7 conditioned by the mutation in the MFSD8 gene. Functional studies showed significantly decreased urate uptake and a mis-localized URAT1 signal in p.G366R, p.L415_G417del and p.T467M. Furthermore, colocalization studies showed accumulation of URAT1 protein in the endoplasmic reticulum. The findings suggest that loss-of-function mutations cause RHUC via loss of UA absorption partly by protein misfolding. However, they do not necessarily lead to AKI and a possible genotype-phenotype correlation was not proposed. Furthermore, results confirm an uneven geographical and ethnic distribution of SLC22A12 variants; the p.L415_G417del mutation predominates in the Roma ethnic group in the Czech Republic.
| S-EPMC3778361 | biostudies-literature