Kazunori Namba1, Hideki Mutai, Yoichiro Takiguchi, Hirotaka Yagi, Takahide Okuyama, Shuntaro Oba, Ryosuke Yamagishi, Hiroki Kaneko, Tomoko Shintani, Kimitaka Kaga, Tatsuo Matsunaga. 1. *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.
Abstract
HYPOTHESIS: 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. CONCLUSION: 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.
HYPOTHESIS: Different missense mutations of the optic atrophy 1 gene (OPA1) identified in optic atrophypatients 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. CONCLUSION: 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.