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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: .
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Does heterozygous Polg mutation cause motor dysfunction due to mtDNA deletions? Context: Mutations in nuclear-encoded mitochondrial DNA (mtDNA) polymerase (POLG) are known to cause autosomal dominant chronic progressive external ophthalmoplegia (adCPEO) with accumulation of multiple mtDNA deletions in muscles. However, no animal model with a heterozygous Polg mutation representing mtDNA impairment and symptoms of CPEO has been established. To understand the pathogenic mechanism of CPEO, it is important to determine the age dependency and tissue specificity of mtDNA impairment resulting from a heterozygous mutation in the Polg gene in an animal model. We assessed behavioral phenotypes, tissue-specific accumulation of mtDNA deletions, and its age dependency in heterozygous Polg (D257A) knock-in mice carrying a proofreading-deficient mutation in the Polg. Heterozygous Polg (D257A) knock-in mice exhibited motor dysfunction in a rotarod test. Polg (+/D257A) mice had significant accumulation of multiple mtDNA deletions, but did not show significant accumulation of point mutations or mtDNA depletion in the brain. While mtDNA deletions increased in an age-dependent manner regardless of the tissue even in Polg (+/+) mice, the age-dependent accumulation of mtDNA deletions was enhanced in muscles and in the brain of Polg (+/D257A) mice.
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Heterozygous Polg (D257A) knock-in mice showed tissue-specific, age-dependent accumulation of multiple mtDNA deletions in muscles and the brain which was likely to result in neuromuscular symptoms. Polg (+/D257A) mice may be used as an animal model of adCPEO associated with impaired mtDNA maintenance. Final Decision: yes