A Missense Mutation in the Murine Opa3 Gene Models Human Inherited Optic Atrophy

Abstract

Purpose: : Opa3 mRNA is expressed in all tissues examined to date, but currently the function of the OPA3 protein is unknown, although a potential role in mitochondrial processes has been proposed. Intriguingly, various mutations in the OPA3 gene lead to two similar, yet distinct diseases in humans: autosomal dominant inherited optic atrophy and cataract (ADOAC) and a metabolic condition; type 3-methylglutaric aciduria (MGA: Costeff Syndrome). 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.

Methods: : 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 B6;C3-opa3L122P, located in exon 2, causes an amino acid change which is predicted to alter tertiary protein structure.

Results: : In the heterozygous state, the mice appear uncompromised, however, in the homozygous state mice display features of MGA &ADOAC. Visual function is severely reduced, attributable to 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 increased COX histochemistry. Mice homozygous for the opa3L122P mutation also display a severe multi-systemic disease characterised by reduced lifespan, decreased weight, dilated cardiomyopathy, extrapyramidal dysfunction and gross neuro-muscular defects.

Conclusions: : These defects are synonymous with the phenotypic characteristics of Type III MGA found in humans. This model will be of major importance for studies of the function of the OPA3 gene and of the human disorders featuring optic atrophy: Type III MGA and ADOAC. It will also contribute to elucidation of the wider role of OPA3 and mitochondrial involvement.

Keywords: optic nerve • genetics • ganglion cells