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

Abstract

A genetic defect in urate transporter 1 (URAT1) is the major cause of renal hypouricemia (RHUC). Although RHUC is detected using a serum uric acid (UA) concentration <2.0 mg/dL, the relationship between the genetic state of URAT1 and serum UA concentration is not clear. Homozygosity and compound heterozygosity with respect to mutant URAT1 alleles are associated with a serum UA concentration of <1.0 mg/dL and are present at a prevalence of ~0.1% in Japan. In heterozygous individuals, the prevalence of a serum UA of 1.1–2.0 mg/dL is much higher in women than in men. The frequency of mutant URAT1 alleles is as high as 3% in the general Japanese population. The expansion of a specific mutant URAT1 allele derived from a single mutant gene that occurred in ancient times is reflected in modern Japan at a high frequency. Similar findings were reported in Roma populations in Europe. These phenomena are thought to reflect the ancient migration history of each ethnic group (founder effects). Exercise-induced acute kidney injury (EI-AKI) is mostly observed in individuals with homozygous/compound heterozygous URAT1 mutation, and laboratory experiments suggested that a high UA load on the renal tubules is a plausible mechanism for EI-AKI.

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

“…Increased 8-OHdG levels were noted in cardiovascular diseases, kidney disease in individuals with type 1 diabetes, and colorectal or serous ovarian cancer [ 222 , 223 , 224 , 225 ]. Hypouricemia may be caused by decreased uric acid production, uric acid oxidation due to treatment with uricase, or decreased renal tubular reabsorption due to inherited or acquired disorders [ 226 , 227 ]. Serum lysine levels (besides other AA) seem to be stable during diet changes, for example, the oxidation of lysine is at similar levels in humans with protein restriction [ 228 ].…”

Uric acid transport, transporters, and their pharmacological targeting

“…Enomoto and coworkers characterized 3 index cases: one with a nonsense mutation (W258X) and two with missense mutations (T217M and E298D) 35 . Since the original description by Enomoto et al, more than 30 mutations causing familial renal hypouricemia have been reported 42 . This condition occurs at higher frequencies in Japanese, Iraqi Jews, and Roma 43–45 .…”

“…This condition occurs at higher frequencies in Japanese, Iraqi Jews, and Roma 43–45 . The higher frequency among the Japanese and the Roma has been attributed to a founder effect in those populations 42 . Genome‐wide association studies (GWAS) have yielded URAT1 polymorphisms in other populations as well 46 .…”

“…35 Since the original description by Enomoto et al, more than 30 mutations causing familial renal hypouricemia have been reported. 42 This condition occurs at higher frequencies in Japanese, Iraqi Jews, and Roma. [43][44][45] The higher frequency among the Japanese and the Roma has been attributed to a founder effect in those populations.…”

Hyperuricemia and Endothelial Function: Is It a Simple Association or Do Gender Differences Play a Role in This Binomial?

“…As regards the cellular transport system of uric acid, it is known that in humans, almost all uric acid is filtered by the glomeruli and reabsorbed from the renal tubules through transporter subunits present on the surface of the glomerular lumen (URAT 1), before reaching the basolateral membrane where the URATv1 transporter is located, which plays an important role in uric acid absorption in endothelial cells [ 27 , 28 ]. Experimental studies have shown that uric acid transporters are also expressed in vascular endothelial cells, contributing to inflammation; oxidative stress; and, hence, endothelial dysfunction through a reduction in endothelial NO [ 29 , 30 ].…”