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A missense mutation in the murine Opa3 gene models human Costeff syndrome

Davies, Vanessa J., Powell, Kathryn A., White, Kathryn E., Yip, Wan Fen, Hogan, Vanessa, Hollins, Andrew John, Davies, Jennifer Rhian, Piechota, Malgorzata, Brownstein, David G., Moat, Stuart James, Nichols, Philip P., Wride, Michael A., Boulton, Michael Edwin and Votruba, Marcela 2008. A missense mutation in the murine Opa3 gene models human Costeff syndrome. Brain 131 (2) , pp. 368-380. 10.1093/brain/awm333

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Abstract

Opa3 mRNA is expressed in all tissues examined to date, but currently the function of the OPA3 protein is unknown. Intriguingly, various mutations in the OPA3 gene lead to two similar diseases in humans: autosomal dominant inherited optic atrophy and cataract (ADOAC) and a metabolic condition; type 3-methylglutaconic aciduria (MGA). Early onset bilateral optic atrophy is a common characteristic of both disorders; retinal ganglion cells are lost and visual acuity is impaired from an early age. In order to investigate the function of the OPA3 protein, we have generated a novel ENU-induced mutant mouse carrying a missense mutation in the OPA3 gene. The heterozygous mutation in exon 2, causes an amino acid change p.L122P (c.365T>C), which is predicted to alter tertiary protein structure. In the heterozygous state, the mice appear uncompromised however; in the homozygous state mice display some of the features of MGA. Visual function is severely reduced, consistent with significant loss of retinal ganglion cells and degeneration of axons in the optic nerve. In the homozygous optic nerve, there was evidence of increased mitochondrial activity, as demonstrated by the increased presence of mitochondrial marker Cytochrome C Oxidase (COX) histochemistry. Mice homozygous for the opa3L122P mutation also display a severe multi-systemic disease characterized by reduced lifespan (majority dying before 4 months), decreased weight, dilated cardiomyopathy, extrapyramidal dysfunction and gross neuro-muscular defects. All of these defects are synonymous with the phenotypic characteristics of Type III MGA found in humans. This model will be of major importance for future studies of the specific function of the OPA3 gene.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Experimental MRI Centre (EMRIC)
Medicine
Optometry and Vision Sciences
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QP Physiology
R Medicine > RE Ophthalmology
Uncontrolled Keywords: OPA3 ; inherited optic atrophy ; 3-methylglutaconic aciduria ; mouse model
Publisher: Oxford University Press
ISSN: 1460-2156
Last Modified: 04 Feb 2018 01:26
URI: http://orca.cf.ac.uk/id/eprint/13293

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