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However, no animal model with a heterozygous Polg mutation representing mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> impairment and symptoms of <jats:styled-content style=\"fixed-case\">CPEO<\/jats:styled-content> has been established. To understand the pathogenic mechanism of <jats:styled-content style=\"fixed-case\">CPEO<\/jats:styled-content>, it is important to determine the age dependency and tissue specificity of mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> impairment resulting from a heterozygous mutation in the <jats:italic>Polg<\/jats:italic> gene in an animal model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed behavioral phenotypes, tissue\u2010specific accumulation of mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> deletions, and its age dependency in heterozygous <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>D257A<\/jats:italic><\/jats:sup> knock\u2010in mice carrying a proofreading\u2010deficient mutation in the <jats:italic>Polg<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Heterozygous <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>D257A<\/jats:italic><\/jats:sup> knock\u2010in mice exhibited motor dysfunction in a rotarod test. <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>+\/D257A<\/jats:italic><\/jats:sup> mice had significant accumulation of multiple mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> deletions, but did not show significant accumulation of point mutations or mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> depletion in the brain. While mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> deletions increased in an age\u2010dependent manner regardless of the tissue even in <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> mice, the age\u2010dependent accumulation of mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> deletions was enhanced in muscles and in the brain of <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>+\/D257A<\/jats:italic><\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Heterozygous <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>D257A<\/jats:italic><\/jats:sup> knock\u2010in mice showed tissue\u2010specific, age\u2010dependent accumulation of multiple mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> deletions in muscles and the brain which was likely to result in neuromuscular symptoms. <jats:italic>Polg<\/jats:italic><jats:sup><jats:italic>+\/D257A<\/jats:italic><\/jats:sup> mice may be used as an animal model of ad<jats:styled-content style=\"fixed-case\">CPEO<\/jats:styled-content> associated with impaired mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> maintenance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.133","type":"journal-article","created":{"date-parts":[[2014,10,22]],"date-time":"2014-10-22T13:15:30Z","timestamp":1413983730000},"page":"909-920","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Heterozygous <i>Polg<\/i> mutation causes motor dysfunction due to mt<scp>DNA<\/scp> deletions"],"prefix":"10.1002","volume":"1","author":[{"given":"Satoshi","family":"Fuke","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Dynamics of Mental Disorders RIKEN Brain Science Institute Wako Saitama Japan 351\u20100198"},{"name":"Department of Integrative 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