title: A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.
abstract: 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.
authors.affiliation: Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinics Tuebingen, Tuebingen, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Grau
authors.forename: Lena F
authors.initials: LF
authors.lastname: Burbulla
authors.forename: Gertraud
authors.initials: G
authors.lastname: Engl
authors.forename: Cécile
authors.initials: C
authors.lastname: Delettre
authors.forename: Benjamin
authors.initials: B
authors.lastname: Delprat
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.forename: Beate
authors.initials: B
authors.lastname: Leo-Kottler
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Doron
authors.initials: D
authors.lastname: Rapaport
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Simone
authors.initials: S
authors.lastname: Schimpf-Linzenbold
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*
chemical_list: C443108:OPA3 protein, human; D011506:Proteins
keywords: Mitochondria; OPA3; Optic Atrophy