Hereditary Renal Hypouricemia (HRH) is usually asymptomatic but can also be complicated by nephrolithiasis or exercise-induced acute kidney injury (EIAKI) (PMID:25966807).
Renal hypouricemia is a common inherited disorder characterized by impaired renal urate reabsorption and subsequent low serum urate levels. It may be associated with severe complications such as exercise-induced acute renal failure and nephrolithiasis (Matsuo et al., 2008). Matsuo ...Renal hypouricemia is a common inherited disorder characterized by impaired renal urate reabsorption and subsequent low serum urate levels. It may be associated with severe complications such as exercise-induced acute renal failure and nephrolithiasis (Matsuo et al., 2008). Matsuo et al. (2008) found hypouricemia in 0.94% of individuals from a large Japanese database
In 3 Japanese individuals, including a mother and son, with hypouricemia, Matsuo et al. (2008) identified 2 different heterozygous mutations in the SLC2A9 gene (606142.0004; 606142.0005). In vitro functional expression studies showed that both mutations resulted in decreased urate ...In 3 Japanese individuals, including a mother and son, with hypouricemia, Matsuo et al. (2008) identified 2 different heterozygous mutations in the SLC2A9 gene (606142.0004; 606142.0005). In vitro functional expression studies showed that both mutations resulted in decreased urate transport activity. - Quantitative Trait Locus for Uric Acid Concentration In a genomewide association study to uncover unconsidered pathways in the regulation of uric acid concentration, Doring et al. (2008) genotyped 1,644 individuals from the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K study population. They observed that the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). Doring et al. (2008) replicated these findings in 3 independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR: Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup of 117 individuals showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women. In a combined analysis of all samples, SNP dbSNP rs7442295 (606142.0001) in intron 6 achieved a P value of 2.97 x 10(-70). A markedly stronger effect in females compared to males was observed in all studies. The major allele, especially in homozygosity, was associated with an increased risk of gout. Vitart et al. (2008) identified genetic variants within the transporter gene SLC2A9 that explained 1.7 to 5.3% of the variance in serum uric acid concentrations, following a genomewide association scan in a Croatian population sample. The authors found serum uric acid to be strongly associated with 7 SNPs, 1 located just 5-prime to SLC2A9 and the others within introns 3 through 7 of this gene. Three of the 6 located within the SLC2A9 gene, dbSNP rs737267 (606142.0003), dbSNP rs13129697, and dbSNP rs6449213 (606142.0002), reached genomewide significance after Bonferroni correction (P = 1.7 x 10(-7) or less). Vitart et al. (2008) found that the dbSNP rs737267 polymorphism explained 5.3% of the total unadjusted variance in serum uric acid concentration in women and 1.7% of the variance in men. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian, and German population samples. Injection of SLC2A9 mRNA into Xenopus oocytes demonstrated that SLC2A9, a known fructose transporter, is considerably more active as a urate transporter. By genomewide linkage analysis of 7,699 participants in the Framingham cohort and in 4,148 participants in a Rotterdam cohort, Dehghan et al. (2008) found a significant association between serum uric acid concentration and dbSNP rs16890979 in the SLC2A9 gene. The findings were replicated in the ARIC cohort of 11,024 white and 3,843 black individuals, yielding p values of 2.3 x 10(-105) and 2.9 x 10(-18), respectively. The combined p value for white individuals from all 3 cohorts was 7.0 x 10(-168), and further analysis showed that the SNP was also associated with the development of gout in white participants (odds ratio of 0.59; p = 7.9 x 10(-14)). The findings confirmed the QTL for serum uric acid concentration on chromosome 4p16. Sulem et al. (2011) tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. Sulem et al. (2011) identified dbSNP rs734553T in the SLC2A9 gene as associated with serum uric acid levels (effect = 0.24 standard deviation, p = 1.0 x 10(-80)), and the risk of gout (odds ratio = 1.39, 5% confidence interval 1.23-1.59, p = 2.4 x 10(-7))