title: Molecular Impairment Mechanisms of Novel OPA1 Mutations Predicted by Molecular Modeling in Patients With Autosomal Dominant Optic Atrophy and Auditory Neuropathy Spectrum Disorder.
abstract: OBJECTIVE
  Different missense mutations of the optic atrophy 1 gene (OPA1) identified in optic atrophy patients with auditory neuropathy spectrum disorder (ANSD) induce functional impairment through different molecular mechanisms.
  
  
  BACKGROUND
  OPA1 is the gene responsible for autosomal dominant optic atrophy (ADOA), but some of its mutations are also associated with ANSD. OPA1 is a member of the GTPase family of proteins and plays a key role in the maintenance of mitochondrial activities that are dependent on dimer formation of the protein. There are many reports of OPA1 mutations, but the molecular mechanisms of their functional impairments are unclear.
  
  
  METHODS
  The sequences of coding regions in OPA1 were analyzed from blood samples of ADOA patients with ANSD. Molecular modeling of the protein's ability to form dimers and its GTP-binding ability were conducted to study the effects of structural changes in OPA1 caused by two identified mutations and their resultant effects on protein function.
  
  
  RESULTS
  Two heterozygous mutations, p.T414P (c.1240A>C) and p.T540P (c.1618A>C), located in the GTPase and middle domains of OPA1, respectively, were identified in two patients. Molecular modeling indicated decreased dimer formation caused by destabilization of the association structure of the p.T414P mutant, and decreased GTP-binding caused by destabilization of the binding site structure in the p.T540P mutant.
  
  
  CONCLUSIONS
  These two different conformational changes might result in decreased GTPase activities that trigger ADOA associated with ANSD, and are likely to be associated with mild clinical features. Molecular modeling would provide useful information in clinical practice.
authors.affiliation: *Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center †Department of Otolaryngology, Eiju General Hospital ‡1st Government and Public Solutions Division, NEC Solution Innovators, Ltd §Graduate School of Integrated Basic Sciences, Nihon University ||Department of Integrated Science in Physics and Biology, College of Humanities and Science, Nihon University, Tokyo ¶Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo #National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Namba
authors.forename: Hideki
authors.initials: H
authors.lastname: Mutai
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yagi
authors.forename: Takahide
authors.initials: T
authors.lastname: Okuyama
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Oba
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yamagishi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shintani
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Kaga
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000328:Adult; D005260:Female; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006313:Hearing Loss, Central / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human