title: New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy.
abstract: BACKGROUND
  Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations.
  
  
  METHODS
  The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model.
  
  
  RESULTS
  Genetic analysis revealed an m.3472T>C transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder.
  
  
  CONCLUSIONS
  This mutation expands the spectrum of deleterious changes in mitochondrial DNA-encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients.
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular and Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain.
authors.forename: Íñigo
authors.initials: Í
authors.lastname: Martínez-Romero
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Herrero-Martín
authors.forename: Laura
authors.initials: L
authors.lastname: Llobet
authors.forename: Sonia
authors.initials: S
authors.lastname: Emperador
authors.forename: Antonio
authors.initials: A
authors.lastname: Martín-Navarro
authors.forename: Bernat
authors.initials: B
authors.lastname: Narberhaus
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Ascaso
authors.forename: Ester
authors.initials: E
authors.lastname: López-Gallardo
authors.forename: Julio
authors.initials: J
authors.lastname: Montoya
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruiz-Pesini
mesh_terms: D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D058609:Visual Field Tests; D014794:Visual Fields
chemical_list: D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human
keywords: Leber hereditary optic neuropathy; mitochondrial DNA; mutation; respiratory complex I