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

Vanessa J. Davies, Kate A. Powell, Kathryn E. White, Wanfen Yip, Vanessa Hogan, Andrew J. Hollins, Jennifer R. Davies, Malgorzata Piechota, David G. Brownstein, Stuart J. Moat, Philip P. Nichols, Michael A. Wride, Michael E. Boulton, Marcela Votruba

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)368-380
Number of pages13
JournalBrain
Volume131
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

Fingerprint

Missense Mutation
Retinal Ganglion Cells
Optic Nerve
Mutation
Genes
Optic Atrophy
Dilated Cardiomyopathy
Electron Transport Complex IV
Tertiary Protein Structure
Visual Acuity
Axons
Exons
Proteins
Amino Acids
Weights and Measures
Messenger RNA
Costeff optic atrophy syndrome
3-Methylglutaconic Aciduria

Keywords

  • 3-methylglutaconic aciduria
  • Inherited optic atrophy
  • Mouse model
  • OPA3

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Davies, V. J., Powell, K. A., White, K. E., Yip, W., Hogan, V., Hollins, A. J., ... Votruba, M. (2008). A missense mutation in the murine Opa3 gene models human Costeff syndrome. Brain, 131(2), 368-380. https://doi.org/10.1093/brain/awm333

A missense mutation in the murine Opa3 gene models human Costeff syndrome. / Davies, Vanessa J.; Powell, Kate A.; White, Kathryn E.; Yip, Wanfen; Hogan, Vanessa; Hollins, Andrew J.; Davies, Jennifer R.; Piechota, Malgorzata; Brownstein, David G.; Moat, Stuart J.; Nichols, Philip P.; Wride, Michael A.; Boulton, Michael E.; Votruba, Marcela.

In: Brain, Vol. 131, No. 2, 02.2008, p. 368-380.

Research output: Contribution to journalArticle

Davies, VJ, Powell, KA, White, KE, Yip, W, Hogan, V, Hollins, AJ, Davies, JR, Piechota, M, Brownstein, DG, Moat, SJ, Nichols, PP, Wride, MA, Boulton, ME & Votruba, M 2008, 'A missense mutation in the murine Opa3 gene models human Costeff syndrome', Brain, vol. 131, no. 2, pp. 368-380. https://doi.org/10.1093/brain/awm333
Davies VJ, Powell KA, White KE, Yip W, Hogan V, Hollins AJ et al. A missense mutation in the murine Opa3 gene models human Costeff syndrome. Brain. 2008 Feb;131(2):368-380. https://doi.org/10.1093/brain/awm333
Davies, Vanessa J. ; Powell, Kate A. ; White, Kathryn E. ; Yip, Wanfen ; Hogan, Vanessa ; Hollins, Andrew J. ; Davies, Jennifer R. ; Piechota, Malgorzata ; Brownstein, David G. ; Moat, Stuart J. ; Nichols, Philip P. ; Wride, Michael A. ; Boulton, Michael E. ; Votruba, Marcela. / A missense mutation in the murine Opa3 gene models human Costeff syndrome. In: Brain. 2008 ; Vol. 131, No. 2. pp. 368-380.
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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.",
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