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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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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).
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).
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.
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.
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