Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy.

TitleRare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy.
Publication TypeJournal Article
Year of Publication2012
AuthorsAchilli, A, Iommarini, L, Olivieri, A, Pala, M, Kashani, BHooshiar, Reynier, P, La Morgia, C, Valentino, MLucia, Liguori, R, Pizza, F, Barboni, P, Sadun, F, De Negri, AMaria, Zeviani, M, Dollfus, H, Moulignier, A, Ducos, G, Orssaud, C, Bonneau, D, Procaccio, V, Leo-Kottler, B, Fauser, S, Wissinger, B, Amati-Bonneau, P, Torroni, A, Carelli, V
JournalPLoS One
Date Published2012
KeywordsAmino Acid Sequence, Base Sequence, Conserved Sequence, DNA, Mitochondrial, Family, Humans, Mitochondrial Proteins, Molecular Sequence Data, Mutation, Optic Atrophy, Hereditary, Leber, Phylogeny, Polymorphism, Restriction Fragment Length, Sequence Alignment, Species Specificity

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.METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.

Alternate JournalPLoS ONE
Citation Key10.1371/journal.pone.0042242
PubMed ID22879922
PubMed Central IDPMC3411744
Grant ListGGP06233 / / Telethon / Italy
GPP10005 / / Telethon / Italy