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Main text We herein report the case of one European family with early onset of hyperuricemia/gout of which female proband was found to have pediatric-onset hyperuricemia associated with a newly identified functionally null variant allele in ATP-binding cassette transporter G2 (ABCG2). Hitherto, we and other groups revealed that the dysfunction of ABCG2—a physiologically important urate exporter expressed in the kidney and intestine— raises the risk of hyperuricemia/gout [1–4]; however, there is little information on this relationship in terms of familial history of early-onset hyperuricemia/gout. Our case will emphasize the importance of ABCG2 genotyping in the risk estimation of early onset of such excess urate-related diseases, which has the potential for clinical application in precision medicine. The pedigree is depicted in Fig. 1a. Detailed information on each subject and related methods are available in Additional file 1. Metabolic investigation for purine metabolism suggested that hyperuricemia in two patients (the family proband II:2 and III:1) was not caused by excess production of uric acid, which led us to focus on the excretion system for urate from the body. To explore the possible causes of this familial hyperuricemia/gout, we addressed ABCG2 genotypes in this family since dysfunction of ABCG2 is the strongest genetic risk factor of hyperuricemia/gout that affects urate excretion. As a result of targeted exon sequencing of ABCG2, two non-synonymous allelic variants of ABCG2— c.34G>A (p.V12M) and c.725T>C (p.I242T, a novel variant)—were found in this family. There were no alreadyknown genetic risk factors for hyperuricemia/gout such as ABCG2 c.376C>T (p.Q126X) and c.421C>A (p.Q141K). Given that p.V12M variant that was only found in the subject III:2 reportedly has no effects on the expression and urate transport activity of ABCG2 [1], we focused on the c.725T>C (p.I242T) in each subject (Fig. 1a). Heterozygous mutation at c.725 T>C was identified in all earlyonset hyperuricemia/gout patients (II:2 and III:1) and one young girl (III:3). She has been on very strict purine/lactose/gluten diet for more than 10 years, which might suppress the elevation of her serum urate (sU) levels. Moreover, subjects I:2 (post-menopausal hyperuricemia woman) and III:2 (generally healthy man) who never showed clinical signs of early onset of hyperuricemia/gout were homozygous of ABCG2 wild-type. Thus, it is conceivable that ABCG2 c.725T>C (p.I242T) associated with the development of early onset of hyperuricemia/gout in this family. Next, we experimentally investigated the effect of this novel non-synonymous mutation (p.I242T) on the intracellular processing and function of ABCG2 protein. A series of biochemical analyses using transiently ABCG2expressing mammalian cells demonstrated that the p.I242T variant had little effect on the protein level and N-glycosylation status of ABCG2 (Fig. 1b) and that, like ABCG2 wild-type, matured-p.I242T variant localized on the plasma membrane as a glycoprotein (Fig. 1c, d). However, functional assay revealed that contrary to the wild-type, the p.I242T variant had no ATP-dependent urate transport activity (Fig. 1e). Moreover, a cell-based urate transport assay supported that the p.I242T variant could hardly excrete urate from cells to extracellular

Familial early-onset hyperuricemia and gout associated with a newly identified dysfunctional variant in urate transporter ABCG2