Pathogenic GLUT9 Mutations Causing Renal Hypouricemia Type 2 (RHUC2)

Abstract

Renal hypouricemia (MIM 220150) is an inherited disorder characterized by low serum uric acid levels and has severe complications such as exercise-induced acute renal failure and urolithiasis. We have previously reported that URAT1/SLC22A12 encodes a renal urate-anion exchanger and that its mutations cause renal hypouricemia type 1 (RHUC1). With the large health-examination database of the Japan Maritime Self-Defense Force, we found two missense mutations (R198C and R380W) of GLUT9/SLC2A9 in hypouricemia patients. R198C and R380W occur in highly conserved amino acid motifs in the "sugar transport proteins signatures" that are observed in GLUT family transporters. The corresponding mutations in GLUT1 (R153C and R333W) are known to cause GLUT1 deficiency syndrome because arginine residues in this motif are reportedly important as the determinants of the membrane topology of human GLUT1. Therefore, on the basis of membrane topology, the same may be true of GLUT9. GLUT9 mutants showed markedly reduced urate transport in oocyte expression studies, which would be the result of the loss of positive charges in those conserved amino acid motifs. Together with previous reports on GLUT9 localization, our findings suggest that these GLUT9 mutations cause renal hypouricemia type 2 (RHUC2) by their decreased urate reabsorption on both sides of the renal proximal tubule cells. However, a previously reported GLUT9 mutation, P412R, was unlikely to be pathogenic. These findings also enable us to propose a physiological model of the renal urate reabsorption via GLUT9 and URAT1 and can lead to a promising therapeutic target for gout and related cardiovascular diseases.

Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9compound heterozygosity

“…In previously documented patients, the recessive p.Gly216Arg mutation was either homozygous or in compound heterozygous patients [7], whereas the p.Arg380Trp substitution was observed only in heterozygosity and was therefore classified as a dominant mutation [11,15]. Comparison of the clinical and biochemical characteristics of our patient with the other recently reported patients provides new insights into the genotype-phenotype correlation of SLC2A9 mutations associated with UA homeostasis.…”

“…Loss of cytoplasmic anchor points of the membrane topology results in a significant reduction in UA transport activity in mutated GLUT9. In addition, the p.Arg380Trp mutation was functionally characterized in the Xenopus model, where it demonstrated a marked reduction of UA transport activity compared to wild type GLUT9 [11,15]. …”

“…Heterozygous SLC2A9 mutations cause hypouricemia mainly via haploinsufficiency [11,12,15]. In a number of studies, homozygous and compound heterozygous loss-of-function mutations have been found to cause severe hypouricemia (serum UA near 0), markedly higher renal excretion, and nephrolithiasis and EIARF in most patients described from different ethnic groups [6,7,10,13,14].…”

Urate transporters in the genomic era

“…This process is energetically favourable and URATv1 transports urate out of the cell in a voltagedependent fashion. As is the case with URAT1, loss-of-function mutations of this transporter cause renal hypouricemia [17][18][19][20][21]. URATv1 has two splice variant isoforms (long and short) [22].…”

“…For example, G774A mutation in SLC22A12 translates into truncated (W258stop) and nonfunctional URAT1 protein, causing renal hypouricemia [2]. Other rare mutants in SLC22A12 [11][12][13] and SLC2A9 [17][18][19][20][21] that cause renal hypouricemia have recently been reported. In the case of ABCG2, a common mutant causing hyperuricemia and gout, Q141K, has been carefully studied [36 && ].…”