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A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network
  1. Tanja Grau1,2,
  2. Lena F Burbulla3,4,
  3. Gertraud Engl5,
  4. Cécile Delettre6,
  5. Benjamin Delprat6,7,
  6. Konrad Oexle8,
  7. Beate Leo-Kottler9,
  8. Tony Roscioli10,
  9. Rejko Krüger3,
  10. Doron Rapaport5,
  11. Bernd Wissinger1,
  12. Simone Schimpf-Linzenbold1
  1. 1Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinics Tuebingen, Tuebingen, Germany
  2. 2Werner Reichardt Centre for Integrative Neuroscience, Institute for Ophthalmology, University of Tuebingen, Tuebingen, Germany
  3. 3Laboratory of Functional Neurogenomics, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
  4. 4German Research Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
  5. 5Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany
  6. 6INSERM U-1051, Institut des Neurosciences de Montpellier, Montpellier, France
  7. 7Université de Montpellier I et II, Montpellier, France
  8. 8Institute of Human Genetics, Technical University Munich, Munich, Germany
  9. 9Department of Ophthalmology, University Eye Hospital Tuebingen, University Clinics Tuebingen, Tuebingen, Germany
  10. 10School of Women's and Children's Health, Sydney Children's Hospital, University of New South Wales, Sydney, Australia
  1. Correspondence to Dr Simone Schimpf-Linzenbold, Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinics Tuebingen, Roentgenweg 11, 72076 Tuebingen, Germany; Simone.Schimpf-Linzenbold{at}


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.

  • Optic Atrophy
  • OPA3
  • Mitochondria

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