1. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network
- Author
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Tanja Grau, Simone Schimpf-Linzenbold, Cécile Delettre, Konrad Oexle, Rejko Krüger, Benjamin Delprat, Doron Rapaport, Gertraud Engl, Beate Leo-Kottler, Tony Roscioli, Bernd Wissinger, Lena F. Burbulla, Molecular Genetics Laboratory [Tuebingen, Germany] (Centre for Ophthalmology), University Clinics Tuebingen [Germany]-Institute for Ophthalmic Research [Tuebingen, Germany], Werner Reichardt Centre for Integrative Neuroscience [Tuebingen, Germany], Tuebingen University [Germany] -Institute for Ophthalmology [Tuebingen, Germany], Laboratory of Functional Neurogenomics [Tuebingen, Germany], Center of Neurology and Hertie-Institute for Clinical Brain Research [Tuebingen, Germany]-University of Tuebingen, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Interfaculty Institute of Biochemistry [Tuebingen, Germany], University of Tuebingen, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1), Université Montpellier 2 - Sciences et Techniques (UM2), Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of Ophthalmology [Tuebingen, Germany], University Eye Hospital Tuebingen-University Clinics Tuebingen, School of Women's and Children's Health [Sydney, Australia], University of New South Wales [Sydney] (UNSW)-Sydney Children's hospital, This work was supported by grants from the Federal Ministry for Education and Research ((BMBF), E-RARE/ERMION: 01GM1006 to BW, NGFNplus, 01GS08134 to RK, MitoNET to DR) and by grants from the Fritz Thyssen Foundation (Az. 10.11.2.153 to RK), the German Research Council (DFG, KR2119/8-1 to RK), the United Mitochondrial Disease Foundation (to DR) and by a doctoral scholarship from the charitable Hertie Foundation (to LFB)., Delprat, Benjamin, Institute for Ophthalmic Research [Tuebingen, Germany]-University Clinics Tuebingen [Germany], University of Tuebingen-Center of Neurology and Hertie-Institute for Clinical Brain Research [Tuebingen, Germany], and Institut des Neurosciences de Montpellier (INM)
- Subjects
Male ,[SDV]Life Sciences [q-bio] ,Mutant ,DNA Mutational Analysis ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Mitochondrion ,OPA3 ,medicine.disease_cause ,pathology [Mitochondria] ,Costeff syndrome ,Cohort Studies ,0302 clinical medicine ,Mutant protein ,cytology [Fibroblasts] ,Genetics (clinical) ,Cells, Cultured ,Genetics ,Aged, 80 and over ,0303 health sciences ,Mutation ,Middle Aged ,Phenotype ,Pedigree ,Mitochondria ,[SDV] Life Sciences [q-bio] ,Female ,Adult ,Adolescent ,genetics [Optic Atrophy, Autosomal Dominant] ,genetics [Mutation] ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,03 medical and health sciences ,Atrophy ,Optic Atrophy, Autosomal Dominant ,Optic Atrophy ,[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,medicine ,Humans ,ddc:610 ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,Aged ,OPA3 protein, human ,Proteins ,Fibroblasts ,metabolism [Mitochondria] ,medicine.disease ,genetics [Proteins] ,Molecular biology ,Mutation testing ,genetics [Mitochondria] ,030217 neurology & neurosurgery - Abstract
International audience; Background: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 mutations, including the mutation spectrum and its prevalence in a large cohort of OPA1-negative autosomal dominant optic atrophy (ADOA) patients, the associated clinical phenotype and the functional characterisation of a newly identified OPA3 mutant.Methods: Mutation analysis was carried out in a patient cohort of 121 independent ADOA patients. To characterise a novel OPA3 mutation, we analysed the mitochondrial import, steady-state levels and the mitochondrial localisation of the mutated protein in patients' fibroblasts. Furthermore, the morphology of mitochondria harbouring the mutated OPA3 was monitored.Results: We identified four independent cases (representing families with multiple affected members) with OPA3 mutations. Besides the known p.Q105E mutation, we observed a novel insertion, c.10_11insCGCCCG/p.V3_G4insAP which is located in the mitochondrial presequence. Detailed functional analysis of mitochondria harbouring this novel mutation demonstrates a fragmented mitochondrial network with a decreased mitochondrial mass in patient fibroblasts. In addition, quantification of the OPA3 protein reveals decreased steady-state levels of the mutant protein compared with the native one. Comparison of the clinical phenotypes suggests that OPA3 mutations can additionally evoke hearing loss and by that extend the clinical manifestation of OPA3-associated optic atrophy. This finding is supported by expression analysis of OPA3 in murine cochlear tissue.Conclusions: In summary, our study provides new insights into the clinical spectrum and the pathogenesis of dominant optic atrophy caused by mutations in the OPA3 gene.
- Published
- 2013
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