Caporali, Leonardo, Ghelli, Anna Maria, Iommarini, Luisa, Maresca, Alessandra, Valentino, Maria Lucia, La Morgia, Chiara, Liguori, Rocco, Zanna, Claudia, Barboni, Piero, De Nardo, Vera, Martinuzzi, Andrea, Rizzo, Giovanni, Tonon, Caterina, Lodi, Raffaele, Calvaruso, Maria Antonietta, Cappelletti, Martina, Porcelli, Anna Maria, Achilli, Alessandro, Pala, Maria, Torroni, Antonio and Carelli, Valerio (2013) Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1832 (3). pp. 445-452. ISSN 09254439

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.