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Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions

OBJECTIVE: 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 represe...

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Autores principales: Fuke, Satoshi, Kametani, Mizue, Yamada, Kazuyuki, Kasahara, Takaoki, Kubota-Sakashita, Mie, Kujoth, Gregory C, Prolla, Tomas A, Hitoshi, Seiji, Kato, Tadafumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265062/
https://www.ncbi.nlm.nih.gov/pubmed/25540805
http://dx.doi.org/10.1002/acn3.133
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author Fuke, Satoshi
Kametani, Mizue
Yamada, Kazuyuki
Kasahara, Takaoki
Kubota-Sakashita, Mie
Kujoth, Gregory C
Prolla, Tomas A
Hitoshi, Seiji
Kato, Tadafumi
author_facet Fuke, Satoshi
Kametani, Mizue
Yamada, Kazuyuki
Kasahara, Takaoki
Kubota-Sakashita, Mie
Kujoth, Gregory C
Prolla, Tomas A
Hitoshi, Seiji
Kato, Tadafumi
author_sort Fuke, Satoshi
collection PubMed
description OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.
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spelling pubmed-42650622014-12-24 Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions Fuke, Satoshi Kametani, Mizue Yamada, Kazuyuki Kasahara, Takaoki Kubota-Sakashita, Mie Kujoth, Gregory C Prolla, Tomas A Hitoshi, Seiji Kato, Tadafumi Ann Clin Transl Neurol Research Articles OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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. BlackWell Publishing Ltd 2014-11 2014-10-22 /pmc/articles/PMC4265062/ /pubmed/25540805 http://dx.doi.org/10.1002/acn3.133 Text en © 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Fuke, Satoshi
Kametani, Mizue
Yamada, Kazuyuki
Kasahara, Takaoki
Kubota-Sakashita, Mie
Kujoth, Gregory C
Prolla, Tomas A
Hitoshi, Seiji
Kato, Tadafumi
Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions
title Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions
title_full Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions
title_fullStr Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions
title_full_unstemmed Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions
title_short Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions
title_sort heterozygous polg mutation causes motor dysfunction due to mtdna deletions
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265062/
https://www.ncbi.nlm.nih.gov/pubmed/25540805
http://dx.doi.org/10.1002/acn3.133
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