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Fuke S, Kametani M, Yamada K, et al. Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions. Ann Clin Transl Neurol. 2014;1(11):909-20doi: 10.1002/acn3.133.
Fuke, S., Kametani, M., Yamada, K., Kasahara, T., Kubota-Sakashita, M., Kujoth, G. C., Prolla, T. A., Hitoshi, S., & Kato, T. (2014). Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions. Annals of clinical and translational neurology, 1(11), 909-20. https://doi.org/10.1002/acn3.133
Fuke, Satoshi, et al. "Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions." Annals of clinical and translational neurology vol. 1,11 (2014): 909-20. doi: https://doi.org/10.1002/acn3.133
Fuke S, Kametani M, Yamada K, Kasahara T, Kubota-Sakashita M, Kujoth GC, Prolla TA, Hitoshi S, Kato T. Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions. Ann Clin Transl Neurol. 2014 Nov;1(11):909-20. doi: 10.1002/acn3.133. Epub 2014 Oct 22. PMID: 25540805; PMCID: PMC4265062.
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Ann Clin Transl Neurol. 2014 Nov;1(11):909-20. doi: 10.1002/acn3.133. Epub 2014 Oct 22.

Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions.

Annals of clinical and translational neurology

Satoshi Fuke, Mizue Kametani, Kazuyuki Yamada, Takaoki Kasahara, Mie Kubota-Sakashita, Gregory C Kujoth, Tomas A Prolla, Seiji Hitoshi, Tadafumi Kato

Affiliations

  1. 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.
  2. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
  3. Research Resources Center, RIKEN Brain Science Institute Wako, Saitama, Japan, 351-0198.
  4. Department of Neurological Surgery, University of Wisconsin Madison, Wisconsin, 53792.
  5. Departments of Genetics and Medical Genetics, University of Wisconsin Madison, Wisconsin, 53706.
  6. Department of Integrative Physiology, Shiga University of Medical Science Otsu, Shiga, Japan, 520-2192.

PMID: 25540805 PMCID: PMC4265062 DOI: 10.1002/acn3.133

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.

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.

References

  1. Science. 1999 Mar 5;283(5407):1482-8 - PubMed
  2. Nat Genet. 2008 Mar;40(3):275-9 - PubMed
  3. Eur J Hum Genet. 2005 Apr;13(4):463-9 - PubMed
  4. Biochim Biophys Acta. 2011 Mar;1807(3):270-4 - PubMed
  5. Cell Mol Life Sci. 2011 Jan;68(2):219-33 - PubMed
  6. Aging Cell. 2009 Aug;8(4):502-6 - PubMed
  7. Am J Med Genet. 2001 Spring;106(1):53-61 - PubMed
  8. Nat Genet. 2001 Jul;28(3):211-2 - PubMed
  9. Nucleic Acids Res. 2002 Nov 1;30(21):4626-33 - PubMed
  10. Mitochondrion. 2013 Jul;13(4):282-91 - PubMed
  11. Nat Genet. 2001 Jul;28(3):223-31 - PubMed
  12. Neuromuscul Disord. 2003 Feb;13(2):162-5 - PubMed
  13. Ann Med. 2005;37(3):222-32 - PubMed
  14. J Biol Chem. 2007 Nov 23;282(47):34525-34 - PubMed
  15. PLoS Genet. 2011 Mar;7(3):e1002028 - PubMed
  16. PLoS One. 2010 Jul 07;5(7):e11468 - PubMed
  17. Lancet. 2004 Sep 4-10;364(9437):875-82 - PubMed
  18. Neuromuscul Disord. 2011 Apr;21(4):272-8 - PubMed
  19. Neurology. 1997 May;48(5):1244-53 - PubMed
  20. Science. 2005 Jul 15;309(5733):481-4 - PubMed
  21. Nat Genet. 2007 Apr;39(4):540-3 - PubMed
  22. Cell Metab. 2010 Dec 1;12(6):675-82 - PubMed
  23. Am J Hum Genet. 2006 Jun;78(6):1026-34 - PubMed
  24. Brain. 2006 Jul;129(Pt 7):1674-84 - PubMed
  25. Nature. 2004 May 27;429(6990):417-23 - PubMed
  26. Arch Neurol. 2007 Apr;64(4):553-7 - PubMed
  27. CNS Drugs. 2007;21(1):1-11 - PubMed
  28. Muscle Nerve. 1996 Dec;19(12):1561-9 - PubMed
  29. J Clin Invest. 1992 Jul;90(1):61-6 - PubMed
  30. Neurology. 1999 Jul 13;53(1):79-84 - PubMed
  31. Exp Cell Res. 2003 Sep 10;289(1):133-42 - PubMed
  32. Mol Psychiatry. 2006 Jun;11(6):577-93, 523 - PubMed
  33. Genes Dev. 2002 Apr 1;16(7):846-58 - PubMed
  34. Neurology. 1998 Jan;50(1):99-106 - PubMed
  35. Cell Metab. 2009 Aug;10(2):131-8 - PubMed
  36. Nucleic Acids Res. 2009 Apr;37(7):2327-35 - PubMed
  37. Neuromolecular Med. 2003;3(3):129-46 - PubMed
  38. Neurology. 2004 Jan 27;62(2):316-8 - PubMed
  39. Hum Mol Genet. 2001 Oct 15;10(22):2469-79 - PubMed
  40. Nat Genet. 2008 Apr;40(4):392-4 - PubMed

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