Renal Hypouricemia 1: Rare Disorder as Common Disease in Eastern Slovakia Roma Population

Abstract

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon–intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.

Identification of a dysfunctional exon-skipping splice variant in GLUT9/SLC2A9 causal for renal hypouricemia type 2

“…Hitherto, we have enrolled dysuricemia (hyperuricemia and hypouricemia) individuals from the Roma populations ( Stiburkova et al, 2016 ; Toyoda et al, 2019 ; Pavelcova et al, 2020 ; Stiburkova et al, 2021 ). In this process, we serendipitously found a family with RHUC of which the proband exhibited severe phenotypes; however, its causality could not be explained by already-characterized genetic variations responsible for RHUC, as described below.…”

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia

“…There were no racial differences in exercise-induced changes in purine metabolism. As noted in the Introduction, although the frequency of RHUC is reported to be higher in the Japanese and in the Roma ethnic group, which is also distributed in the Czech Republic [ 8 ], there are no reports of differences in the symptoms of RHUC or the frequency of EIAKI.…”

“…The world’s highest frequency of predominant dysfunctional RHUC1 variants was identified in the common European Roma population (1125 subjects): the rs200104135 (p.T467M) variant has a frequency of 5.76%, and the deletion variant p.L415_G417 (no available in public databases) has a frequency of 1.73%. RHUC is asymptomatic, but it can cause clinical complications, such as exercise-induced acute kidney injury (EIAKI) and urinary tract stones [ 7 , 8 , 9 ]. The hypothesized cause of the renal failure is that RHUC with low UA is affected by ROS and causes renal ischemia due to vasoconstriction.…”

Genetic Basis of the Epidemiological Features and Clinical Significance of Renal Hypouricemia

“…Among Roma populations and in Korea, where the same URAT1 mutant alleles were repeatedly identified, lower frequencies of GLUT9 mutant alleles than of URAT1 mutant alleles were reported [ 24 , 25 , 26 ]. In China, screening of the URAT1 and GLUT9 genes for mutations was performed in 31 individuals with hypouricemia (SUA concentration ≤2.0 mg/dL) selected from the general population [ 27 ], and this showed that the number of people with GLUT9 mutations was lower than that of people with URAT1 mutations (two vs. four, no mutations in the URAT1 or GLUT9 genes were found in the other 25 individuals).…”