title: Functional Characterization of Three Concomitant MtDNA LHON Mutations Shows No Synergistic Effect on Mitochondrial Activity.
abstract: The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations.
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cruz-Bermúdez
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Ramiro J
authors.initials: RJ
authors.lastname: Vicente-Blanco
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Rosana
authors.initials: R
authors.lastname: Hernández-Sierra
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
authors.forename: Mayte
authors.initials: M
authors.lastname: Montero
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Alvarez
authors.affiliation: Hospital de Móstoles, Universidad Rey Juan Carlos, 28935, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: González Manrique
authors.affiliation: Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Blázquez
authors.affiliation: Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martín
authors.affiliation: Department of Genetics, IIS-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain, and Centro de Investigacion Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Fernández-Moreno
mesh_terms: D000328:Adult; D002460:Cell Line; D019069:Cell Respiration; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial