Brain Advance Access originally published online on February 21, 2007
Brain 2007 130(4):1029-1042; doi:10.1093/brain/awm005
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A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy
1Molecular Genetics Laboratory, 2Department of Pathophysiology of Vision and Neuro-Ophthalmology, 3Section for Experimental Vitreoretinal Surgery, University Eye Hospital, 4Retinal Diagnostics Research Group, University Eye Hospital, Tuebingen, 5Molecular Neurobiology, Tuebingen Hearing Research Center (THRC), Department of Otorhinolaryngology, University of Tuebingen, 6Laboratory for Preclinical Imaging and Imaging Technology, Department of Radiology and 7Ingenium Pharmaceuticals AG, Martinsried, Germany
Correspondence to: E-mail: wissinger{at}uni-tuebingen.de
Autosomal dominant optic atrophy (adOA) is a juvenile onset, progressive ocular disorder characterized by bilateral loss of vision, central visual field defects, colour vision disturbances, and optic disc pallor. adOA is most frequently associated with mutations in OPA1 encoding a dynamin-related large GTPase that localizes to mitochondria. Histopathological studies in adOA patients have shown a degeneration of retinal ganglion cells (RGCs) and a loss of axons in the optic nerve. However little is known about the molecular mechanism and pathophysiology of adOA due to the lack of appropriate in vivo models. Here we report a first mouse model carrying a splice site mutation (c.1065 + 5G 
A) in the Opa1 gene. The mutation induces a skipping of exon 10 during transcript processing and leads to an in-frame deletion of 27 amino acid residues in the GTPase domain. Western blot analysis showed no evidence of a shortened mutant protein but a 
50% reduced OPA1 protein level supporting haploinsufficiency as a major disease mechanism in adOA. Homozygous mutant mice die in utero during embryogenesis with first notable developmental delay at E8.5 as detected by magnetic resonance imaging (MRI). Heterozygous mutants are viable and of normal habitus but exhibit an age-dependent loss of RGCs that eventually progresses to a severe degeneration of the ganglion cell and nerve fibre layer. In addition optic nerves of mutant mice showed a reduced number of axons, and a swelling and abnormal shape of the remaining axons. Mitochondria in these axons showed disorganized cristae structures. All these defects recapitulate crucial features of adOA in humans and therefore document the validity and importance of this model for future research.
Key Words: adOA; OPA1; splice site mutation; mitochondria; mouse model
Abbreviations: adOA, autosomal dominant optic atrophy; ENU, N-ethyl-N-nitrosourea; MEFs, mouse embryonic fibroblasts; MRI, magnetic resonance imaging; OPA1, optic atrophy gene 1; RGC, retinal ganglion cell
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Received August 25, 2006. Revised December 3, 2006. Accepted January 5, 2007.
*These authors contributed equally to this work.
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