HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: iovs.09-3634v1 50/10/4561    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Yu-Wai-Man, P. Articles by Chinnery, P. F. Search for Related Content PubMed PubMed Citation Articles by Yu-Wai-Man, P. Articles by Chinnery, P. F.

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

¹From the Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, and ⁶Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom; ²Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; ³Cardiff Neuroscience Centre and ⁴School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom; and ⁵Cardiff Eye Unit, University Hospital of Wales, Cardiff, United Kingdom.

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 C57Bl/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 C57Bl/6 controls with both 2° and 8° gratings (P < 0.001). At age 18 months, the difference between the two groups was significant for the 8° grating (P = 0.003) but not for the 2° 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.

This article has been cited by other articles:

				P. Yu-Wai-Man, P.G. Griffiths, G.S. Gorman, C.M. Lourenco, A.F. Wright, M. Auer-Grumbach, A. Toscano, O. Musumeci, M.L. Valentino, L. Caporali, et al. Multi-system neurological disease is common in patients with OPA1 mutations Brain, March 1, 2010; 133(3): 771 - 786. [Abstract] [Full Text] [PDF]