Abstract
Inosine triphosphate pyrophosphatase (ITPase), the enzyme that hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding purine nucleoside monophosphate and pyrophosphate, is encoded by the Itpa gene. In this study, we established Itpa knockout (KO) mice and used them to show that ITPase is required for the normal organization of sarcomeres in the heart. Itpa−/− mice died about 2 weeks after birth with features of growth retardation and cardiac myofiber disarray, similar to the phenotype of the cardiac α-actin KO mouse. Inosine nucleotides were found to accumulate in both the nucleotide pool and RNA of Itpa−/− mice. These data suggest that the role of ITPase in mice is to exclude ITP from the ATP pool, and the main target substrate of this enzyme is rITP. Our data also suggest that cardiomyopathy, which is mainly caused by mutations in sarcomeric protein-encoding genes, is also caused by a defect in maintaining the quality of the ATP pool, which is an essential requirement for sarcomere function.
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Abbreviations
- ITPase:
-
inosine triphosphate pyrophosphatase
- RBCs:
-
red blood cells
- KO:
-
knockout
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Acknowledgements
We thank Dr. M Katsuki for CCE ES cells, Dr. Y Nakatsu for discussion, Y Yamada, M Sasaki, M Otsu, S Kitamura and A Matsuyama for technical assistance and Dr. W Campbell for comments on the manuscript. This study was supported by grants from Core Research for Evolutional Science and Technology (to YN), the Japan Science and Technology Agency, the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18012035, 20012038 to KS), and the Japan Society for the Promotion of Science (19651097 to KS and 19390114 to DT).
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Behmanesh, M., Sakumi, K., Abolhassani, N. et al. ITPase-deficient mice show growth retardation and die before weaning. Cell Death Differ 16, 1315–1322 (2009). https://doi.org/10.1038/cdd.2009.53
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DOI: https://doi.org/10.1038/cdd.2009.53
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