title: A novel m.7539C>T point mutation in the mt-tRNA(Asp) gene associated with multisystemic mitochondrial disease.
abstract: Mitochondrial transfer RNA (mt-tRNA) mutations are the commonest sub-type of mitochondrial (mtDNA) mutations associated with human disease. We report a patient with multisytemic disease characterised by myopathy, spinal ataxia, sensorineural hearing loss, cataract and cognitive impairment in whom a novel m.7539C>T mt-tRNA(Asp) transition was identified. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for the mutation whilst single muscle fibre segregation studies revealed statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres. Absence from control databases, hierarchical mt-tRNA mutation segregation within tissues, and occurrence at conserved sequence positions, further confirm this novel mt-tRNA mutation to be pathogenic. To date only three mt-tRNA(Asp) gene mutations have been described with clear evidence of pathogenicity. The novel m.7539C>T mt-tRNA(Asp) gene mutation extends the spectrum of pathogenic mutations in this gene, further supporting the notion that mt-tRNA(Asp) gene mutations are associated with multisystemic disease presentations.
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Ernst-Grube-Str. 40, Halle/Saale 06097, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Lehmann
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Ernst-Grube-Str. 40, Halle/Saale 06097, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schubert
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Ernst-Grube-Str. 40, Halle/Saale 06097, Germany.
authors.forename: Pushpa R
authors.initials: PR
authors.lastname: Joshi
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Baty
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Ernst-Grube-Str. 40, Halle/Saale 06097, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zierz
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Ernst-Grube-Str. 40, Halle/Saale 06097, Germany. Electronic address: marcus.deschauer@uk-halle.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
mesh_terms: D001921:Brain / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D017354:Point Mutation; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012349:RNA, Transfer, Asp / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012349:RNA, Transfer, Asp; D012313:RNA; D003576:Electron Transport Complex IV
keywords: Mitochondria; Multisystemic disease; tRNA(Asp)