Diagnostic Tests for Primary Renal Hypouricemia

Abstract

Primary renal hypouricemia is a genetic disorder characterized by defective renal uric acid (UA) reabsorption with complications such as nephrolithiasis and exercise-induced acute renal failure. The known causes are: defects in the SLC22A12 gene, encoding the human urate transporter 1 (hURAT1), and also impairment of voltage urate transporter (URATv1), encoded by SLC2A9 (GLUT9) gene. Diagnosis is based on hypouricemia (<119 μmol/L) and increased fractional excretion of UA (>10%). To date, the cases with mutations in hURAT1 gene have been reported in East Asia only. More than 100 Japanese patients have been described. Hypouricemia is sometimes overlooked; therefore, we have set up the flowchart for this disorder. The patients were selected for molecular analysis from 620 Czech hypouricemic patients. Secondary causes of hyperuricosuric hypouricemia were excluded. The estimations of (1) serum UA, (2) excretion fraction of UA, and (3) analysis of hURAT1 and URATv1 genes follow. Three transitions and one deletion (four times) in SLC22A12 gene and one nucleotide insertion in SLC2A9 gene in seven Czech patients were found. Three patients had acute renal failure and urate nephrolithiasis. In addition, five nonsynonymous sequence variants and three nonsynonymous sequence variants in SLC2A9 gene were found in two UK patients suffering from acute renal failure. Our finding of the defects in SLC22A12 and SLC2A9 genes gives further evidence of the causative genes of primary renal hypouricemia and supports their important role in regulation of serum urate levels in humans.

High frequency of SLC22A12 variants causing renal hypouricemia 1 in the Czech and Slovak Roma population; simple and rapid detection method by allele-specific polymerase chain reaction

“…Recent studies have suggested that RHUC is not necessarily restricted to East Asian populations, as previously thought. Loss-of-function mutations affecting URAT1 have also been found in Caucasian populations in Macedonia, the United Kingdom, and the Czech Republic [4,5,10,11]. Additionally, case reports from European patients with symptoms of RHUC have also been previously reported [12,13].…”

“…We recently identified and functionally characterized three novel variants in the SLC22A12 gene in Czech RHUC patients [4][5][6]. Our findings of two c.1245_1253del heterozygous individuals in a control cohort of 109 subjects from the Roma population suggested the existence of prevalent variant in this minority population in the Czech Republic.…”

Absence of SLC22A12/URAT1 Gene Mutations in Patients with Primary Gout

“…The first urate transporter described was SLC22A12/URAT1 1 . Mutations in the SLC22A12/URAT1 gene have been associated to primary renal hypouricemia type I (OMIN 220150) in several populations 1,2,3,4,5 , although some ethnic differences may explain the lack of association between this gene and primary renal hypouricemia in other populations such as Greek whites 6 . Because this transporter reabsorbs urate from the renal tubule, loss of function mutations may cause renal urate wasting and hypouricemia.…”

Genetic Disorders Resulting in Hyper- or Hypouricemia

“…Confirmation of the diagnosis is accomplished by molecular analysis of the SCL22A12 and SLC2A9 genes. [31][32][33] Therapy is based on alkalization of urine, increased fluid intake, and avoidance of strenuous exercise. 29 For patients in whom no mutation has been found, referral to an academic medical center will help further research in this disorder and provide useful information for affected families.…”