| Summary: | Introduction: OPA3 is the causative gene of the autosomal recessive, multi-systemic neuro- ophthalmological syndrome, 3-methylglutaconic aciduria Type III (MGA-III) and Autosomal Dominant Optic Atrophy and Cataract (ADOAC). Early onset bilateral optic atrophy is a common characteristic of both disorders where retinal ganglion cells (RGCs) are lost. Purpose: To investigate the pathophysiology of the disease and function of the OPA3 protein we generated a novel ENU-induced mutant mouse carrying the missense mutation p.L122P in exon 2 of Opa3 which is predicted to alter tertiary protein structure. Methods: Visual function was assessed using optokinetic nystagmus and pupillary light reflex. Histology explored retinal degeneration and metabolic dysfunction. Rotarod, wirehang and open field analysed neurological, neuromuscular and behavioural aspects of the disease. Genomic structure of Opa3 was re-examined using RT-PCR and bio-informatic programs characterized possible upstream transcription factor binding sites (TFBS). Results: Opa3 ' mice displayed a multi-systemic disease, including decreased life span and weight, extra-pyramidal dysfunction, neuro-muscular defect, craniofacial defects, reduction in intra-abdominal white adipose tissue, elevated marrow adiposity and severe hepatic steatosis. Opa3'' are functionally blind but pupillary function was essentially intact. Histology showed loss of RGCs and other cell types through postnatal development onwards. RT-PCR identified a third exon and analysis of 53 TFBS identified suggests a role for Opa3 in retinal and craniofacial development, cellular stress response/apoptosis and adipogenesis. Conclusions: Opa3 / display many aspects of human MGA-III syndrome and phenotypes not observed such as craniofacial defects and a profound disturbance in lipid metabolism. Opa3 is thought to be involved in the mevalonate shunt and leucine degradation metabolic pathways. Defects in these pathways can cause a build up of 3-methylglutaconic acid and 3- methylglyaric acid in the inner mitochondrial membrane which may have a profound affect on mitochondrial metabolism particularly in high energy demand tissues such as retina, heart and neurons.
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