Genetic Analysis of Human Urate Transporter 1 (hURAT1) and Glucose Transporter 9 (GLUT9) in Taiwanese Patients with Idiopathic Renal Hypouricemia

Abstract

Background: The phenotypic characteristics of idiopathic renal hypouricemia (IRH) include impaired renal uric acid re-absorption, low serum uric acid levels, and severe complications such as exercise-induced acute renal failure (EIARF) and nephrolithiasis. IRH is increasingly reported to be associated with inactivating mutations in either SLC22A12 gene encoding the human urate acid transporter 1 (hURAT1) or 5LC2A9 gene encoding glucose transporter 9 (GLUT9) in proximal tubules. Mutations in hURAT1 or GLUT9 have not been reported in Taiwanese patients with IRH. Purpose: To investigate the phenotypic and genetic characteristics in Taiwanese patients with IRH. Patients: Six Taiwanese patients (5 males and 1 female, mean age 30±23 years) with hypouricemia (serum uric acid concentration＜2.3 mg/dL) and concomitant excessive renal uric acid excretion (FE(subscript UA)＞10%) from five unrelated families were enrolled. Their clinical symptoms and biochemical studies were recorded. Methods: Molecular analysis of both SLC22A12 and 5LC2A9 genes was performed by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and direct sequencing. Results: Serum uric acid concentration was 1.16±0.23 mg/dl with a fractional excretion of uric acid of 61±12%. Two male patients experienced exercise-induced acute renal failure requiring hemodialysis. None of them had nephrocalcinosis or uric acid stone. Despite a negative mutation in 5LC2J49, four novel SLC22A12 mutations (W120R, M2 15L, T2 17M and T467M) and one recurrent homozygous (R90H) mutations were identified in five patients. Conclusion: EIARF can develop in Taiwanese patients with IRH, and most of them are males. Mutations in 5LC22A 12 rather than 5LC2A9 cause IRH in patients with FE(subscript UA)＜100%. Other candidate genes need to be identified for IRH patients without 5LC22J4 12 and SLC2A9 gene mutations.