PMID- 25540805
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20141225
LR  - 20181113
IS  - 2328-9503 (Print)
IS  - 2328-9503 (Electronic)
IS  - 2328-9503 (Linking)
VI  - 1
IP  - 11
DP  - 2014 Nov
TI  - Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions.
PG  - 909-20
LID - 10.1002/acn3.133 [doi]
AB  - 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.
FAU - Fuke, Satoshi
AU  - Fuke S
AD  - 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.
FAU - Kametani, Mizue
AU  - Kametani M
AD  - Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science 
      Institute Wako, Saitama, Japan, 351-0198.
FAU - Yamada, Kazuyuki
AU  - Yamada K
AD  - Research Resources Center, RIKEN Brain Science Institute Wako, Saitama, Japan, 
      351-0198.
FAU - Kasahara, Takaoki
AU  - Kasahara T
AD  - Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science 
      Institute Wako, Saitama, Japan, 351-0198.
FAU - Kubota-Sakashita, Mie
AU  - Kubota-Sakashita M
AD  - Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science 
      Institute Wako, Saitama, Japan, 351-0198.
FAU - Kujoth, Gregory C
AU  - Kujoth GC
AD  - Department of Neurological Surgery, University of Wisconsin Madison, Wisconsin, 
      53792.
FAU - Prolla, Tomas A
AU  - Prolla TA
AD  - Departments of Genetics and Medical Genetics, University of Wisconsin Madison, 
      Wisconsin, 53706.
FAU - Hitoshi, Seiji
AU  - Hitoshi S
AD  - Department of Integrative Physiology, Shiga University of Medical Science Otsu, 
      Shiga, Japan, 520-2192.
FAU - Kato, Tadafumi
AU  - Kato T
AD  - Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science 
      Institute Wako, Saitama, Japan, 351-0198.
LA  - eng
PT  - Journal Article
DEP - 20141022
PL  - United States
TA  - Ann Clin Transl Neurol
JT  - Annals of clinical and translational neurology
JID - 101623278
PMC - PMC4265062
EDAT- 2014/12/30 06:00
MHDA- 2014/12/30 06:01
PMCR- 2014/10/22
CRDT- 2014/12/26 06:00
PHST- 2014/06/25 00:00 [received]
PHST- 2014/09/25 00:00 [revised]
PHST- 2014/09/25 00:00 [accepted]
PHST- 2014/12/26 06:00 [entrez]
PHST- 2014/12/30 06:00 [pubmed]
PHST- 2014/12/30 06:01 [medline]
PHST- 2014/10/22 00:00 [pmc-release]
AID - 10.1002/acn3.133 [doi]
PST - ppublish
SO  - Ann Clin Transl Neurol. 2014 Nov;1(11):909-20. doi: 10.1002/acn3.133. Epub 2014 
      Oct 22.