May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Opa1 Mutations Induce Mitochondrial Dna Instability and Optic Atrophy Plus Phenotypes
Author Affiliations & Notes
  • V. Carelli
    Neurology, University of Bologna, Bologna, Italy
  • P. Reynier
    Département de Biochimie et Génétique, Centre Hospitalier Universitaire d’Angers; INSERM U694, Angers, France
  • M. L. Valentino
    Neurology, University of Bologna, Bologna, Italy
  • R. Carroccia
    Neurology, University of Bologna, Bologna, Italy
  • L. Iommarini
    Neurology, University of Bologna, Bologna, Italy
  • C. La Morgia
    Neurology, University of Bologna, Bologna, Italy
  • R. Garesse
    4Departamento de Bioquimica Instituto de Investigaciones Biomedicas "Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autonoma, Madrid, Spain
  • G. Lenaers
    Institut des Neurosciences de Montpellier, 5INSERM U583, Universités de Montpellier I et II, Montpellier, France
  • D. Bonneau
    Département de Biochimie et Génétique, Centre Hospitalier Universitaire d’Angers; INSERM U694, Angers, France
  • P. Amati-Bonneau
    Département de Biochimie et Génétique, Centre Hospitalier Universitaire d’Angers; INSERM U694, Angers, France
  • Footnotes
    Commercial Relationships  V. Carelli, None; P. Reynier, None; M.L. Valentino, None; R. Carroccia, None; L. Iommarini, None; C. La Morgia, None; R. Garesse, None; G. Lenaers, None; D. Bonneau, None; P. Amati-Bonneau, None.
  • Footnotes
    Support  Supported by Telethon-Italy (grant# GGP06233 to VC)
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5388. doi:https://doi.org/
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      V. Carelli, P. Reynier, M. L. Valentino, R. Carroccia, L. Iommarini, C. La Morgia, R. Garesse, G. Lenaers, D. Bonneau, P. Amati-Bonneau; Opa1 Mutations Induce Mitochondrial Dna Instability and Optic Atrophy Plus Phenotypes. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5388. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : To describe the molecular and clinical features of patients with syndromic optic atrophy and evidence of mitochondrial dysfunction. Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal dominant trait (DOA).

Methods: : We here report on eight patients from six families, most of which had evidence of autosomal dominant inheritance, with a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia (CPEO) and mitochondrial myopathy with cytochrome c oxidase negative and ragged red Fibers. Molecular analysis was carried out on mitochondrial DNA (mtDNA) extracted from the muscle biopsies by southern blot and long-range PCR. The complete sequence of the OPA1 gene was also performed, as well as of the nuclear genes previously involved in mtDNA multiple deletions (POLG1, Twinkle and ANT1).

Results: : We demonstrate that these patients all harboured variable amounts of multiple deletions of mtDNA in their skeletal muscle. All six probands also harboured heterozygous missense mutations in the OPA1 gene affecting highly conserved amino acid positions, five of them being located in the GTPase domain. On the contrary, the sequence analysis of POLG1, Twinkle and ANT1 did not reveal pathogenic defects.

Conclusions: : We show the unprecedented finding that missense OPA1 mutations, not predicted to produce protein truncation and haploinsufficiency, are associated with mtDNA multiple deletions and result in a DOA plus phenotype. This seems to be defined by a combination of optic atrophy and sensorineural deafness, and CPEO with mitochondrial myopathy, cerebellar or spinocerebellar ataxia and peripheral axonal neuropathy. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.

Keywords: neuro-ophthalmology: optic nerve • mitochondria • genetics 
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