title: Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions.
abstract: Complex I (CI) deficiency is a frequent cause of mitochondrial disorders and, in most cases, is due to mutations in CI subunit genes encoded by mitochondrial DNA (mtDNA). In this study, we establish the pathogenic role of the heteroplasmic mtDNA m.3890G>A/MT-ND1 (p.R195Q) mutation, which affects an extremely conserved amino acid position in ND1 subunit of CI. This mutation was found in a young-adult male with optic atrophy resembling Leber's hereditary optic neuropathy (LHON) and bilateral brainstem lesions. The only previously reported case with this mutation was a girl with fatal infantile Leigh syndrome with bilateral brainstem lesions. Transfer of the mutant mtDNA in the cybrid cell system resulted in a marked reduction of CI activity and CI-dependent ATP synthesis in the presence of a normally assembled enzyme. These findings establish the pathogenicity of the m.3890G>A/MT-ND1 mutation and remark the link between CI mutations affecting the mtDNA-encoded ND subunits and LHON-like optic atrophy, which may be complicated by bilateral and symmetric lesions affecting the central nervous system. Peculiar to this mutation is the distribution of the brainstem lesions, with sparing of the striatum in both patients.
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ghelli
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maresca
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanna
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Vera
authors.initials: V
authors.lastname: De Nardo
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Caterina
authors.initials: C
authors.lastname: Tonon
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Calvaruso
authors.forename: Martina
authors.initials: M
authors.lastname: Cappelletti
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Achilli
authors.forename: Maria
authors.initials: M
authors.lastname: Pala
authors.forename: Antonio
authors.initials: A
authors.lastname: Torroni
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D006822:Hybrid Cells; D007773:Lactates / Q000097:blood; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D020125:Mutation, Missense; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D015418:Optic Atrophies, Hereditary / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D004272:DNA, Mitochondrial; D007773:Lactates; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human