title: Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy.
abstract: BACKGROUND
  Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined.
  
  
  RESULTS
  In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I.
  
  
  CONCLUSIONS
  Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.
authors.affiliation: Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Achilli
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Anna
authors.initials: A
authors.lastname: Olivieri
authors.forename: Maria
authors.initials: M
authors.lastname: Pala
authors.forename: Baharak
authors.initials: B
authors.lastname: Hooshiar Kashani
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Federico
authors.initials: F
authors.lastname: Sadun
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: De Negri
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
authors.forename: Antoine
authors.initials: A
authors.lastname: Moulignier
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Ducos
authors.forename: Christophe
authors.initials: C
authors.lastname: Orssaud
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.forename: Beate
authors.initials: B
authors.lastname: Leo-Kottler
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.forename: Antonio
authors.initials: A
authors.lastname: Torroni
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D005190:Family; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010802:Phylogeny; D012150:Polymorphism, Restriction Fragment Length; D016415:Sequence Alignment; D013045:Species Specificity
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins