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M. Alavi, S. Bette, S. Schimpf, F. Schuettauf, U. Schraermeyer, N. Tanimoto, H. F. Wehrl, M. Knipper, J. Laufs, B. Wissinger; A Murine Opa1 Mutant Features Pathology of Autosomal Dominant Optic Atrophy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2463.
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Mutations in the OPA1 gene are a major cause of autosomal dominant optic atrophy (adOA). Here we report the identification and characterization of the first mouse mutant with a pathogenic Opa1 mutation.
A sperm archive of ENU-mutagenized mice was screened for mutations in Opa1 and a mutant strain established by in vitro fertilization. Opa1 transcript and protein levels in various tissues as well as mitochondrial DNA content were assessed by quantitative restriction fragment length polymorphism (RFLP) analysis, real time PCR and western blotting, respectively. Mutant mice were furthermore thoroughly characterized with respect to visual and hearing function, magnetic resonance imaging (MRI), histology of the retina and the optic nerve and quantitative analyses of retinal ganglion cell (RGC) loss.
We identified and established a mouse mutant with a heterozygous splice mutation (c.1065 + 5G>A) in the Opa1 gene. This mutation leads to complete skipping of exon 10 and results in an in-frame deletion of 27 amino acid residues (p.329-355del) in Opa1’s GTPase domain. On transcript levels mRNA from both alleles are equal abundant, while Opa1 protein levels are reduced to 50%. The mitochondrial DNA content was not altered. Homozygous mutant mice are not viable and die during embryogenesis around E8.5 - the stage when the neural fold starts closing! ERG responses were normal in heterozygous mutant mice, as well as auditory function. Histological analysis revealed an erratic loss of RGCs in Opa1 mice at the age of 17 months. A progressive loss of RGCs was confirmed and quantified by retrograde labelling with hydroxystilbamidine. Electron-micrographs of the optic nerve revealed a reduced number of axons, and swelling and distortion of the remaining axons. Furthermore, alterations in the mitochondrial cristae structure of mutant mice are found.
Our Opa1 mouse displays typical adOA features of RGC loss and degeneration of optic nerve axons.
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