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Secondary mtDNA Defects Do Not Cause Optic Nerve Dysfunction in a Mouse Model of Dominant Optic Atrophy

Lookup NU author(s): Dr Patrick Yu Wai Man, Dr Lynsey Cree, Professor Patrick Chinnery


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PURPOSE. The majority of patients with autosomal dominant optic atrophy (DOA) harbor pathogenic OPA1 mutations and certain missense mutations, mostly within the GTPase domain, have recently been shown to cause multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle. This raises the possibility that the optic neuropathy could be the result of secondary mtDNA defects accumulating within retinal ganglion cells (RGCs). To explore this hypothesis, the authors looked for evidence of mitochondrial dysfunction in a mouse model of DOA and documented the visual and neurologic progression in aging mutant mice. METHODS. Visual function was assessed with a rotating optokinetic (OKN) drum at ages 13 and 18 months and neurologic phenotyping was performed using the primary SHIRPA screen at age 13 months, comparing mutant Opa1(+/-) mice with wild-type C57B1/6 mice. The presence of cytochrome c oxidase (COX) deficiency and multiple mtDNA deletions was investigated in gastrocnemius muscle and eye specimens harvested from 2- and 11-month-old Opa1(+/+) and Opa1(+/-) mice. RESULTS. At age 13 months, Opa1(+/-) mice had a statistically significant reduction in OKN responses compared to C57B1/6 controls with both 2 degrees and 8 degrees gratings (P < 0.001). At age 18 months, the difference between the two groups was significant for the 8 degrees grating (P = 0.003) but not for the 2 degrees grating (P = 0.082). Opa1(+/-) mice did not exhibit any significant neuromuscular deficits and no COX deficient areas or secondary mtDNA deletions were identified in skeletal muscle or the RGC layer. There was also no evidence of significant mtDNA depletion or proliferation in skeletal muscle from Opa1(+/-) mice. CONCLUSIONS. COX deficiency and mtDNA abnormalities do not contribute to optic nerve dysfunction in pure DOA. (Invest Ophthalmol Vis Sci. 2009; 50: 4561-4566) DOI:10.1167/iovs.093634

Publication metadata

Author(s): Yu Wai Man P, Davies VJ, Piechota MJ, Cree LM, Votruba M, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Investigative Ophthalmology and Visual Science

Year: 2009

Volume: 50

Issue: 10

Pages: 4561-4566

ISSN (print):

ISSN (electronic):

Publisher: Association for Research in Vision and Ophthalmology


DOI: 10.1167/iovs.09-3634


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