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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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-87751-9 |
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| Summary: | 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. |
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| ISSN: | 2045-2322 |