Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice
Abstract In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene (XDH), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh(− / −) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or x...
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2025-01-01
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| author | Kazuki Terada Tamaki Watanabe Nobuhiro Yasuno Toshio Ohtsubo Shigeru Shibata Kimiyoshi Ichida Makoto Hosoyamada |
| author_facet | Kazuki Terada Tamaki Watanabe Nobuhiro Yasuno Toshio Ohtsubo Shigeru Shibata Kimiyoshi Ichida Makoto Hosoyamada |
| author_sort | Kazuki Terada |
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| description | Abstract In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene (XDH), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh(− / −) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh(− / −) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene (Slc23a4), which is a pseudogene in humans. Hprt(high)Xdh(− / −)Slc23a4(− / −) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt(high)Xdh(− / −)Slc23a4(− / −) mice was lower than that of patients with type 1 xanthinuria. Hprt(high)Xdh(− / −)Slc23a4(− / −) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt(high)Xdh(− / −)Slc23a4(− / −) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh(− / −) mice survive to adulthood. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-60098416d4314641a29cf53af1168b582025-01-26T12:32:04ZengNature PortfolioScientific Reports2045-23222025-01-0115111110.1038/s41598-025-87751-9Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient miceKazuki Terada0Tamaki Watanabe1Nobuhiro Yasuno2Toshio Ohtsubo3Shigeru Shibata4Kimiyoshi Ichida5Makoto Hosoyamada6Laboratory of Human Physiology and Pathology, Faculty of Pharmaceutical Sciences, Teikyo UniversityLaboratory of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Teikyo UniversityLaboratory of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Teikyo UniversityJapanese Red Cross Fukuoka HospitalDivision of Nephrology, Department of Internal Medicine, Teikyo University School of MedicineChiba Health Promotion Center, East Japan Railway CompanyLaboratory of Human Physiology and Pathology, Faculty of Pharmaceutical Sciences, Teikyo UniversityAbstract In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene (XDH), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh(− / −) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh(− / −) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene (Slc23a4), which is a pseudogene in humans. Hprt(high)Xdh(− / −)Slc23a4(− / −) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt(high)Xdh(− / −)Slc23a4(− / −) mice was lower than that of patients with type 1 xanthinuria. Hprt(high)Xdh(− / −)Slc23a4(− / −) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt(high)Xdh(− / −)Slc23a4(− / −) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh(− / −) mice survive to adulthood.https://doi.org/10.1038/s41598-025-87751-9Xanthine dehydrogenaseSodium dependent nucleobase transporterHypoxanthineXanthineType 1 xanthinuria |
| spellingShingle | Kazuki Terada Tamaki Watanabe Nobuhiro Yasuno Toshio Ohtsubo Shigeru Shibata Kimiyoshi Ichida Makoto Hosoyamada Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice Scientific Reports Xanthine dehydrogenase Sodium dependent nucleobase transporter Hypoxanthine Xanthine Type 1 xanthinuria |
| title | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice |
| title_full | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice |
| title_fullStr | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice |
| title_full_unstemmed | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice |
| title_short | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice |
| title_sort | pseudogenization of the slc23a4 gene is necessary for the survival of xdh deficient mice |
| topic | Xanthine dehydrogenase Sodium dependent nucleobase transporter Hypoxanthine Xanthine Type 1 xanthinuria |
| url | https://doi.org/10.1038/s41598-025-87751-9 |
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