Analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations

Analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations in the SLC2A9 gene: p.Arg380Trp, already identified in heterozygosity, and p.Gly216Arg, previously found in homozygosity or compound heterozygosity in some RHUC2 patients. Compared with previously reported patients harbouring these mutations, our proband showed the highest FE-UA levels, suggesting that the combination of p.Arg380Trp and p.Gly216Arg mutations most severely affects the renal handling of UA. Conclusions: The clinical and molecular findings from this patient and a review of the literature provide new insights into the genotype-phenotype correlation of this disorder, supporting the evidence of an autosomal recessive inheritance pattern for RHUC2. Further investigations into the functional properties of GLUT9, URAT1 and other urate transporters are required to assess their potential research and clinical implications. Keywords: Renal hypouricemia, Exercise-induced acute renal failure, SLC2A9 mutations, p.Arg380Trp, p.Gly216ArgBackground Renal hypouricemia is a heterogeneous genetic disorder characterized by impaired tubular transport, reabsorption insufficiency and/or accelerated secretion of uric acid (UA) accompanied by severe complications, such as exerciseinduced acute renal failure (EIARF), chronic kidney disease (CKD) and nephrolithiasis. Diagnosis of renal hypouricemia is based on biochemical markers, i.e., hypouricemia and increased fractional excretion of UA (FE-UA).* Correspondence: [email protected] Equal contributors 2 Division of Biology and PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28381880 Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy Full list of author information is available at the end of the articleRenal hypouricemia type 1 (RHUC1, MIM#220150) is a recessive condition caused by mutations in the SLC22A12 gene encoding the transporter URAT1, which leads to a partial UA absorption defect [1-5]. Renal hypouricemia type 2 (RHUC2, MIM#612076) is a disorder caused by defects in the SLC2A9 gene encoding the facilitative glucose transporter 9 (GLUT9). Heterozygous RHUC2 patients show UA values similar to those of patients with URAT1 mutations, while homozygous and/or compound heterozygous patients have considerably lower serum UA levels (near 0 mg/dl) [normal range 2.35?.90 mg/dl] and higher renal UA excretion (>100 ) [normal range 4?4 ] [6,7].?2014 Jeannin et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution FCCP site License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Jeannin et al. BMC Medical Genetics 2014, 15:3 http://www.biomedcentral.com/1471-2350/15/Page 2 ofMore than 100 patients with mutations in the SLC22A12 gene have been described, whereas only a few patients with defects in the SLC2A9 gene have been characterized. SLC22A12 and SLC2A9 are the two genes that most commonly influence the serum level of UA, exerting their effect by modifying renal UA absorption [1,8]. The SLC22A12 gene encodes two transcript variants of the URAT1 transporter, and both variants are specifically expressed on the apic.