A missense mutation in the murine Opa3 gene models human Costeff syndrome
1School of Optometry and Vision Sciences, Cardiff University, Cardiff, 2Neurology, Medical School, Newcastle upon Tyne, 3Research Animal Pathology Core Facility, University of Edinburgh, UK, 4Department of Medical Biochemistry and Immunology, University Hospital of Wales, Cardiff, UK, 5Zoology Department, School of Natural Sciences, University of Dublin Trinity College, Dublin 2, Ireland, 6Department of Ophthalmology and Vision Sciences, University of Texas Medical Branch, Galveston, TX, USA and 7Cardiff Eye Unit, University Hospital Wales, Cardiff, UK
Correspondence to: Marcela Votruba, School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cathays, Cardiff CF24 4LU, UK E-mail: votrubam{at}cardiff.ac.uk
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.
Key Words: OPA3; inherited optic atrophy; 3-methylglutaconic aciduria; mouse model
Abbreviations: ADOA, autosomal dominant optic atrophy; ADOAC, autosomal dominant optic atrophy and cataract; CMT4A, Charcot–Marie-Tooth type 4A; CMT2A, Charcot–Marie-Tooth type 2A; COX, cytochrome C oxidase; DAB, 3,3'-diaminobenzidine; ENU, N-ethyl-N-nitrosourea; FRDA, Friedreich's ataxia; H&E, haematoxylin and eosin; HMSN VI, hereditary motor and sensory neuropathy type VI; INL, inner nuclear layer; IPL, inner plexiform layer; mfn, mitofusin; MGA, type 3-methylglutaric aciduria; MRC, medical research council; MTP, mitochondrial trifunctional protein; NBF, neutral buffered formalin; NF, neurofilament; NFL, nerve fibre layer; MRI, magnetic resonance imaging; OKN, optokinetic drum; ONL, outer nuclear layer; PINK1, PTEN-induced kinase 1; RGCs, retinal ganglion cells; , SmithKline Beecham Pharmaceuticals; Harwell, MRC Mouse Genome Centre and Mammalian Genetics Unit; , Imperial College School of Medicine at St Mary's; Royal London Hospital, St Bartholomew's and the Royal London School of Medicine; , Phenotype Assessment (SHIRPA)
Received September 21, 2007. Revised December 17, 2007. Accepted December 18, 2007.
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