title: Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198 ; Department of Integrative Physiology, Shiga University of Medical Science Otsu, Shiga, Japan, 520-2192.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fuke
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
authors.forename: Mizue
authors.initials: M
authors.lastname: Kametani
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
authors.forename: Takaoki
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
authors.forename: Mie
authors.initials: M
authors.lastname: Kubota-Sakashita
authors.affiliation: Department of Neurological Surgery, University of Wisconsin Madison, Wisconsin, 53792.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Kujoth
authors.affiliation: Departments of Genetics and Medical Genetics, University of Wisconsin Madison, Wisconsin, 53706.
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.affiliation: Department of Integrative Physiology, Shiga University of Medical Science Otsu, Shiga, Japan, 520-2192.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitoshi
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato