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

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 opa3(L122P) 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.

Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation

“…Fibroblasts of an ADOAC patient harboring an OPA3 mutation (G93S) were more susceptible to apoptotic stimuli [10], and a mouse model of human Costeff syndrome induced by an OPA3 mutation (L122P) is also characterized by loss of retinal ganglion cells and degeneration of optic nerve axons [12]. In the present study, mutant OPA3 (G93S) increased cell death and mitochondrial fragmentation in the absence of apoptotic stimuli.…”

Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation

“…Whether she has true lipodystrophy (abnormal growth and/or loss of adipose tissue due to a primary, intrinsic defect of the tissue) as opposed to lipoatrophy (loss of adipose tissue secondary to hypermetabolism) could not be established with certainty, though her relatively high metabolic rate suggests the possibility of the former. Mouse models with a homozygous mutation in Opa3 showed a 60% reduction in body weight and profound intra-abdominal leanness, suggesting that the patient's loss of adipose tissue may be caused by her OPA3 mutation (Davies et al 2008; Wells et al 2012; Navein et al 2016). The atypical set of phenotypes observed in this case expands the phenotypic spectrum of autosomal dominant mutations in OPA3 and identifies a de novo mutation, which we believe to be pathogenic for these phenotypes.…”

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

“…A mouse model of Costeff Syndrome caused by an Opa3 point mutation was recently described (Davies et al, 2008). Opa3 -/-mice display worse optic nerve defects than opa3 ZM/ZM mutants, and a variety of movement disorders, including extrapyramidal dysfunction.…”

“…Second, several other optic atrophy disorders and one form of MGA (Barth Syndrome/MGA II, OMIM 302060) are caused by mutations in proteins required for IMM functional integrity (Huizing et al, 2005). Third, a mouse model of Costeff Syndrome has mitochondrial defects (Davies et al, 2008). Based on this evidence, the current clinical recommendation is for individuals with Costeff Syndrome to avoid medications known to impair mitochondrial function or to increase oxidative stress (Gunay-Aygun et al, 2010).…”