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Cecile Delettre, Laetitia Buret, Guy Rebillard, Marie Pequignot, Marcio Do-cruzeiro, Karen Cornille, Marc Lenoir, Patricia Amati-Bonneau, Christian Hamel, Guy Lenaers; Mutations In Opa8 Are Associated With Mild Optic Atrophy And Severe Deafness. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5879.
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Dominant optic atrophy (DOA) is the most common form of inherited optic neuropathy. DOA affects retinal ganglion cells (RGCs) and the axons forming the optic nerve, leading to progressive visual loss. Today, there is no treatment able to stop the degenerative process. Unless several loci are implied only two genes have been identified: OPA1 and OPA3. Using a candidate gene strategy on a cohort of OPA1-OPA3 negative patients, we found that a new gene, herein called "OPA8" is mutated in a dominant family with mild optic neuropathy and severe sensorineural deafness. In order to understand the physiopathology of optic and auditive neuropathy linked to OPA8 mutations, we have generated a mutant mouse reproducing a pathogenic mutation.
To generate mutant mouse we obtained gene trap ES cell line that expressed a mutant allele of Opa8. These ES cells harbored a genetrap (GT) cassette in intron 1. Visual function of mutant mouse has been tested by electroretinogram (ERG) and visual evoked potential (VEP) and the auditory function by auditory evoked potential (AEP) and endocochlear potential (EP). To determine the role of OPA8 mutations we studied mitochondrial network and apoptosis in fibroblasts cultures from patients skin biopsies.
OPA8 plays a role in the control of apoptosis. Consistent with this function we have shown that OPA8 mutated fibroblasts are more sensitive to apoptotic stimuli and present fragmented mitochondrial network. Moreover, overexpression of the protein is protecting against apoptosis, while that of the mutated protein is not. OPA8 protein is preponderant in sensory neurons: it is expressed in the RGCs and the bipolar cells of retina and in the spiral ganglion neuron in the cochlea. The mutant mice present a stable auditory impairment of 15 to 20 decibels, whereas there is no visual defect or loss of neurons.
Study of the Opa8 mutant mouse did not reveal such a severe clinical presentation, as no alteration of the vision was detected and only a mild alteration of the audition, but shed light on OPA8 involvement in sensory disease.
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