A Novel Homozygous <b><i>SLC2A9</i></b> Mutation Associated with Renal-Induced Hypouricemia

Abstract

Background: Hereditary renal hypouricemia (RHUC) is a genetically heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA; acute kidney injury (AKI) and nephrolithiasis are recognized complications. Type 1 (RHUC1) is caused by mutations in the SLC22A12 gene, whereas RHUC2 is caused by mutations in the SLC2A9 gene. Patient ethnicity is diverse but only few Caucasian families with an SLC2A9 mutation have been reported. Methods: The current report describes the clinical history, biochemical and molecular genetics findings of a native Austrian family with RHUC2. The propositus presented with 2 episodes of exercise-induced AKI and exhibited profound hypouricemia. Mutational screening of the SLC22A12 and SLC2A9 genes was performed. Results: The molecular analyses revealed the homozygous c.512G>A transition that leads to the p.Arg171His missense substitution in SLC2A9, confirming the diagnosis of RHUC2. Segregation study of the causal mutation revealed that the mother and elder sister were heterozygous carriers, whereas the younger sister was found to be homozygous. Conclusion: We report the identification of a novel mutation in SLC2A9 as the cause of RHUC2 in a native Austrian family. We show that glucose transporter 9 mutations cause severe hypouricemia in homozygous individuals and confirm the high risk of AKI in male individuals harbouring these mutations. In our literature review, we provide an overview of the putative underlying pathophysiology, potential renal complications, findings on kidney biopsy as well as potential long-time renal sequelae.

Tubular and genetic disorders associated with kidney stones

“…Patients with homozygous GLUT9 mutations present with more pronounced hypouricemia and are more prone to nephrolithiasis, and AKI after exercise. However, the underlying mechanism for AKI is still unknown; mechanisms such as urate nephropathy or increased oxidative stress during exercise with renovascular spasm and vasoconstriction leading to renal tissue damage have been proposed [44,43]. Typical histological and imaging findings of repeated vasoconstriction in kidney biopsies from patients with GLUT9 mutations are supportive of the oxidative stress/vasoconstriction hypothesis [45,43].…”

“…Hereditary renal hypouricemia is caused by recessive mutations in two different genes, SLC22A1 and SLC2A9, encoding the proximal renal tubular urate transporter 1, URAT1, and what was originally thought to be a glucose transporter, GLUT9, respectively [43]. However, GLUT9 belongs to the family of GLUT proteins that mediate transepithelial transport of monosaccharides and represents the only member that also and preferentially transports urate.…”

“…However, the underlying mechanism for AKI is still unknown; mechanisms such as urate nephropathy or increased oxidative stress during exercise with renovascular spasm and vasoconstriction leading to renal tissue damage have been proposed [44,43]. Typical histological and imaging findings of repeated vasoconstriction in kidney biopsies from patients with GLUT9 mutations are supportive of the oxidative stress/vasoconstriction hypothesis [45,43]. Therapy consists of adequate fluid intake during exercise and, interestingly, allopurinol, which has been reported to be beneficial by reducing the load of filtered urate [46], but may also have something to do with its intrinsic antioxidant properties.…”

Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview

“…Several rare inherited disorders of XOR deficiency cause an abnormally low level of SUA and a high serum level of xanthine, termed hypouricemia and xanthinuria, respectively [ 27 ]. Hereditary genetic mutations of the urate transporter URAT1 (RHUC1) and glucose transporter 9 (GLUT9; RHUC2) have been reported to cause hypouricemia due to deficiency of reabsorption of kidney-filtered uric acid [ 28 , 29 ]. It may also be caused by uric acid oxidation due to treatment with uricase, or decreased renal tubular reabsorption due to acquired disorders [ 30 ] ( Figure 4 ).…”

Amplicon targeted resequencing for SLC2A9 and SLC22A12 identified novel mutations in hypouricemia subjects

“…Notably, most published literatures on hypouricemia focused on case report or case serials (Zhou et al, 2018), which lack essential statistics through comparison with normal controls and may result in false reports of causative mutations to hypouricemia, especially in the Han Chinese population. Moreover, most reported hRHUC patients were mainly diagnosed using traditional Sanger sequencing (Kim et al, 2015;Windpessl, Ritelli, Wallner, & Colombi, 2016) or locus-specific polymerase chain reaction (PCR) reaction (Takagi, Omae, Makanga, Kawahara, & Inazu, 2013) for one gene SLC22A12 or SLC2A9. Although sanger sequencing is the golden standard for DNA detection but is time-consuming and laborious (Sommen & Van Camp, 2013), next-generation sequencing (NGS) based targeted resequencing has evolved to correctly diagnose genetic diseases in a more cost-effective and time-saving mode (Adams & Eng, 2018;Sommen & Van Camp, 2013).…”