Hypouricemia, Renal, 2

A number sign (#) is used with this entry because of evidence that renal hypouricemia-2 (RHUC2) is caused by homozygous mutation in the SLC2A9 gene (606142) on chromosome 4p16. Some patients have been reported with heterozygous mutations in SLC2A9.

Description

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 (EIARF) and nephrolithiasis (summary by Matsuo et al., 2008).

For additional phenotypic information and a discussion of genetic heterogeneity of renal hypouricemia, see RHUC1 (220150).

Clinical Features

Bahat et al. (2009) and Dinour et al. (2010) reported a large multigenerational consanguineous Israeli-Arab family in which 6 individuals had severe renal hypouricemia. The proband was an 18-year-old man who presented with exercise-induced acute renal failure associated with very low serum uric acid. The fractional excretion of uric acid was 215% (normal range, 5.5 to 8.5%). Renal ultrasound showed hyperechogenic kidneys with no stones. Five additional family members had extremely low hypouricemia and high fractional excretion of uric acid: 2 had a history of EIARF and 2 reported renal stones. Dinour et al. (2010) also reported a 69-year-old man, born of consanguineous Ashkenazi Jewish parents, with RHUC2. Routine examination showed extremely low serum uric acid levels. He had a history of one episode of renal colic and nephrolithiasis approximately 30 years earlier, but no history of renal failure. One of his daughters had hypouricemia, but was unavailable for genetic studies.

Dinour et al. (2012) reported 3 children, born of consanguineous Israeli-Arab parents, with RHUC2 confirmed by genetic analysis. All had very low serum uric acid and high fractional excretion of uric acid, but were asymptomatic. An unrelated 84-year-old man with autosomal recessive RHUC was also asymptomatic. The findings indicated that some individuals with the disorder may be asymptomatic, thus expanding the phenotypic spectrum associated with SLC2A9 mutations.

Inheritance

The transmission pattern of RHUC2 in the family reported by Bahat et al. (2009) and Dinour et al. (2010) was consistent with autosomal recessive inheritance.

Molecular Genetics

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 transport activity.

In affected members of a large consanguineous Israeli-Arab family with autosomal recessive renal hypouricemia-2, Dinour et al. (2010) identified a homozygous missense mutation in the SLC2A9 gene (L75R; 606142.0007). In vitro functional expression studies showed that the mutation markedly decreased the transport of uric acid. A homozygous truncating mutation (606142.0008) was also identified in a man of Ashkenazi Jewish descent with the disorder. The findings were consistent with a loss of function. The patients had very low serum uric acid concentration and a fractional excretion of uric acid over 150%. These patients had lower uric acid levels than those with renal hypouricemia resulting from mutations in the SLC22A12 gene (607096), indicating that the impact of SLC2A9 deficiency exceeds that of SLC22A12, and consistent with observations that uric acid uptake by SLC2A9 is higher than that of SLC22A12. Dinour et al. (2010) speculated that uric acid efflux is mediated solely by basolateral SLC2A9, such that loss of function in this transporter results in a total reabsorption defect.

In 3 sibs, born of consanguineous Israeli-Arab parents, with RHUC2, Dinour et al. (2012) identified a homozygous missense mutation in the SLC2A9 gene (R171C; 606142.0009). An unrelated patient with the disorder carried a different homozygous missense mutation (T125M; 606142.0010). In vitro functional expression studies showed that both mutant proteins had significantly reduced uric acid transport activity compared to controls. All of the patients were clinically asymptomatic. Dinour et al. (2012) noted that the heterozygous parents of the sibs were clinically asymptomatic and had normal serum uric acid levels and normal fractional excretion of uric acid, which conflicted with a previous report of heterozygous mutation carriers having decreased serum uric acid (Matsuo et al., 2008). The degree of uric acid reabsorption in heterozygous mutation carriers must vary depending on other genetic or nongenetic factors.

In a 30-year-old man from the island of Crete with renal hypouricemia-2 and recurrent EIARF, Androvitsanea et al. (2015) identified a homozygous intragenic deletion in the SLC2A9 gene (606142.0011).

Serum Uric Acid Concentration Quantitative Trait Locus 2

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 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, rs737267 (606142.0003), rs13129697, and rs6449213 (606142.0002), reached genomewide significance after Bonferroni correction (P = 1.7 x 10(-7) or less). Vitart et al. (2008) found that the 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 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 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)).