Human Molecular Genetics Advance Access originally published online on April 11, 2007
Human Molecular Genetics 2007 16(11):1307-1318; doi:10.1093/hmg/ddm079
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Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function
1 School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK, 2 Neurology, Medical School, Newcastle upon Tyne, UK, 3 Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA and 4 Cardiff Eye Unit, University Hospital Wales, Cardiff, UK
* To whom correspondence should be addressed at: School of Optometry and Vision Sciences, Redwood Building, King Edward VII Avenue, Cathays Park, Cardiff University, Cardiff CF10 3NB, UK. Tel: +44 2920870134; Fax: +44 2920874859; Email: votrubam{at}cardiff.ac.uk
Received December 11, 2006; Revised February 5, 2007; Accepted March 21, 2007
OPA1 is a ubiquitously expressed, nuclear dynamin-related GTPase, targeted to the inner mitochondrial membrane, which plays a role in mitochondrial fusion. Mutations in the OPA1 gene on chromosome 3q28-qter are associated with autosomal dominant optic atrophy (ADOA), the most common inherited optic neuropathy, in which retinal ganglion cells (RGCs) are lost and visual acuity is impaired from an early age. We have generated a novel ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in opa1 in order to explore the pathophysiology of ADOA. The heterozygous mutation, B6; C3-Opa1Q285STOP, located in exon 8 immediately before the central dynamin-GTPase, leads to 
50% reduction in opa1 protein in retina and all tissues on western analysis. The homozygous mutation is embryonic lethal by 13.5 days post coitum, demonstrating the importance of Opa1 during early development. Fibroblasts taken from adult heterozygous mutant mice show an apparent alteration in morphology, with an increase in mitochondrial fission and fragmentation. Heterozygous mutants show a slow onset of degeneration in the optic nerve electron microscopy. Furthermore, they demonstrate a functional reduction in visual function on testing with the optokinetic drum and the circadian running wheel. These findings indicate that the opa1 GTPase contains crucial information required for the survival of RGCs and that Opa1 is essential for early embryonic survival. The Opa1 +/– mice described here provide a means to directly investigate the cellular pathophysiology of OPA1 ADOA.
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