Slc22a12, also known as URAT1, encodes an uric acid reabsorption transporter. It is crucial in the regulation of serum urate levels as urate transporters in the kidney and gut tightly regulate the excretion and reabsorption of uric acid [1,3,7]. This gene is associated with the metabolic pathway of uric acid and is of great biological importance for maintaining the body's internal balance of uric acid [1,3]. Genetic models can be valuable for studying its function.

Meta-analysis has shown that certain SLC22A12 alleles like rs3825018, rs7932775, and rs475688 are significantly associated with hyperuricemia risk, with rs3825018 and rs3825016 being risk factors under the allelic model, rs7932775 under dominant and recessive models, and rs475688 being protective under both dominant and recessive models [2]. Also, loss-of-function mutations in SLC22A12 can cause renal hypouricemia type 1, a rare hereditary disorder characterized by low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure [4,5,8,9]. Additionally, in clear cell renal cell carcinoma (ccRCC), SLC22A12 is downregulated, and its low expression is related to a poor prognosis, higher pathological stage, and is involved in metabolism, cell cycle, and tumor-related signaling pathways [6].

In conclusion, Slc22a12 is essential for regulating uric acid levels through its role as an uric acid reabsorption transporter. Studies on gene variants and loss-of-function mutations in genetic models have revealed its significance in hyperuricemia, renal hypouricemia, and ccRCC. Understanding Slc22a12 contributes to the understanding of the mechanisms underlying these diseases and may provide potential targets for treatment.

References:

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2. Zheng, Qu, Keliang, Wu, Hongtao, Qiu, Xiaosheng, Lin. . Genetic Association Between SLC22A12 Variants and Susceptibility to Hyperuricemia: A Meta-Analysis. In Genetic testing and molecular biomarkers, 26, 81-95. doi:10.1089/gtmb.2021.0175. https://pubmed.ncbi.nlm.nih.gov/35225677/

3. Matsubayashi, Masaya, Sakaguchi, Yoshihiko M, Sahara, Yoshiki, Umetani, Michihisa, Mori, Eiichiro. . 27-Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35, e21262. doi:10.1096/fj.202002077R. https://pubmed.ncbi.nlm.nih.gov/33368618/

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5. Yim, Jisook, Kim, Myungshin, Suh, Jin-Soon. 2021. Hereditary renal hypouricemia with SLC22A12 mutation: A case report. In Pediatrics and neonatology, 63, 202-203. doi:10.1016/j.pedneo.2021.08.012. https://pubmed.ncbi.nlm.nih.gov/34756726/

6. Xu, Jiaju, Liu, Yuenan, Liu, Jingchong, Yang, Xiong, Zhang, Xiaoping. 2021. Low Expression Levels of SLC22A12 Indicates a Poor Prognosis and Progresses Clear Cell Renal Cell Carcinoma. In Frontiers in oncology, 11, 659208. doi:10.3389/fonc.2021.659208. https://pubmed.ncbi.nlm.nih.gov/34249694/

7. Nigam, Sanjay K. . The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease. In Annual review of pharmacology and toxicology, 58, 663-687. doi:10.1146/annurev-pharmtox-010617-052713. https://pubmed.ncbi.nlm.nih.gov/29309257/

8. Peris Vidal, Amelia, Marin Serra, Juan, Lucas Sáez, Elena, Trujillo-Suarez, Jorge, Fons Moreno, Jaime. 2019. [Not Available]. In Nefrologia, 39, 355-361. doi:10.1016/j.nefro.2018.08.010. https://pubmed.ncbi.nlm.nih.gov/30704753/

9. Perdomo-Ramirez, Ana, Cordoba-Lanus, Elizabeth, Trujillo-Frias, Carmen Jane, Garcia-Nieto, Victor, Claverie-Martin, Felix. 2023. Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M). In International journal of molecular sciences, 24, . doi:10.3390/ijms24098455. https://pubmed.ncbi.nlm.nih.gov/37176161/