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Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber's hereditary optic neuropathy.
Caporali, Leonardo; Iommarini, Luisa; La Morgia, Chiara; Olivieri, Anna; Achilli, Alessandro; Maresca, Alessandra; Valentino, Maria Lucia; Capristo, Mariantonietta; Tagliavini, Francesca; Del Dotto, Valentina; Zanna, Claudia; Liguori, Rocco; Barboni, Piero; Carbonelli, Michele; Cocetta, Veronica; Montopoli, Monica; Martinuzzi, Andrea; Cenacchi, Giovanna; De Michele, Giuseppe; Testa, Francesco; Nesti, Anna; Simonelli, Francesca; Porcelli, Anna Maria; Torroni, Antonio; Carelli, Valerio.
Afiliação
  • Caporali L; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Iommarini L; Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy.
  • La Morgia C; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Olivieri A; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • Achilli A; Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy.
  • Maresca A; Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy.
  • Valentino ML; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Capristo M; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Tagliavini F; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • Del Dotto V; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Zanna C; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Liguori R; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • Barboni P; Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy.
  • Carbonelli M; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Cocetta V; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • Montopoli M; Studio Oculistico D'Azeglio, Bologna, Italy.
  • Martinuzzi A; Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
  • Cenacchi G; Studio Oculistico D'Azeglio, Bologna, Italy.
  • De Michele G; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy.
  • Testa F; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy.
  • Nesti A; IRCCS "E. Medea" Scientific Institute Conegliano-Pieve di Soligo Research Center, Pieve di Soligo, Italy.
  • Simonelli F; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • Porcelli AM; Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples "Federico II", Naples, Italy.
  • Torroni A; Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Carelli V; Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
PLoS Genet ; 14(2): e1007210, 2018 02.
Article em En | MEDLINE | ID: mdl-29444077
We here report on the existence of Leber's hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband's fibroblasts into the cybrid cell model. Finally, all but one of these missense mtDNA variants cluster along the same predicted fourth E-channel deputed to proton translocation within the transmembrane domain of Complex I, involving the ND1, ND4L and ND6 subunits. Hence, the definition of the pathogenic role of a specific mtDNA mutation becomes blurrier than ever and only an accurate evaluation of mitogenome sequence variation data from the general population, combined with functional analyses using the cybrid cell model, may lead to final validation. Our study conclusively shows that even in the absence of a clearly established LHON primary mutation, unprecedented combinations of missense mtDNA variants, individually known as polymorphisms, may lead to reduced OXPHOS efficiency sufficient to trigger LHON. In this context, we introduce a new diagnostic perspective that implies the complete sequence analysis of mitogenomes in LHON as mandatory gold standard diagnostic approach.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA Mitocondrial / Penetrância / Mutação de Sentido Incorreto / Herança Multifatorial / Atrofia Óptica Hereditária de Leber Tipo de estudo: Prognostic_studies Limite: Adult / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA Mitocondrial / Penetrância / Mutação de Sentido Incorreto / Herança Multifatorial / Atrofia Óptica Hereditária de Leber Tipo de estudo: Prognostic_studies Limite: Adult / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article