{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC22A12 encodes the urate transporter 1 (URAT1), a key protein expressed in the apical membrane of renal proximal tubular cells that mediates reabsorption of uric acid from the tubular lumen into the blood, thereby playing a central role in maintaining normal serum urate concentrations. URAT1 functions as an anion exchanger and is the target of clinically used uricosuric agents; its activity can also be modulated by drugs such as losartan, which exerts a uricosuric effect by inhibiting URAT1‐mediated reabsorption."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, URAT1 exhibits substrate specificity for urate and related anions, and its function is facilitated by interactions with accessory proteins such as PDZK1, which enhances its expression and transport activity on the cell surface. Detailed mapping studies have identified key residues that contribute to high‐affinity binding of both the substrate and inhibitors. Moreover, transport assays have demonstrated that URAT1 not only handles urate but also transports additional substrates (for example, orotate), and its inhibition by uricosuric agents like benzbromarone confirms its critical role as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have uncovered a spectrum of loss‐of‐function mutations and non‐synonymous variants in SLC22A12 that impair URAT1 function, leading to conditions such as idiopathic renal hypouricemia. These mutations disrupt uric acid reabsorption, provoke an increased fractional excretion of urate, and can predispose affected individuals to renal stone formation or even exercise‐induced acute kidney injury. Functional analyses in diverse populations have characterized variants with markedly reduced transport activity, underscoring the role of URAT1 in both normal urate homeostasis and pathophysiological states. Some investigations have also noted that while other members of the solute carrier family participate in a variety of metabolic processes, the loss‐of‐function alleles in SLC22A12 remain a distinct molecular marker for altered urate handling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "24"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLarge-scale genetic association studies and genome-wide analyses in various ethnic groups have further established the clinical significance of URAT1. Variants in SLC22A12 are strongly associated with serum urate levels and gout risk, and many population-based studies have demonstrated that nonfunctional or reduced-function alleles of URAT1 confer protection against hyperuricemia and gout. In addition, these investigations have revealed ethnic and geographic differences in allele frequencies, as well as interactions between genetic risk, environmental factors (such as alcohol consumption), and therapeutic interventions that target URAT1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "42"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Atsushi Enomoto, Hiroaki Kimura, Arthit Chairoungdua, et al. 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