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

Alessandro Achilli, Luisa Iommarini, Anna Olivieri, Maria Pala, Baharak Hooshiar Kashani, Pascal Reynier, Chiara La Morgia, Maria Lucia Valentino, Rocco Liguori, Fabio Pizza, Piero Barboni, Federico Sadun, Anna Maria de Negri, Massimo Zeviani, Helene Dollfus, Antoine Moulignier, Ghislaine Ducos, Christophe Orssaud, Dominique Bonneau, Vincent Procaccio & 6 others Beate Leo-Kottler, Sascha Fauser, Bernd Wissinger, Patrizia Amati-Bonneau, Antonio Torroni, Valerio Carelli

Research output: Contribution to journalArticle

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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. 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.

LanguageEnglish
Article numbere42242
JournalPLoS One
Volume7
Issue number8
DOIs
Publication statusPublished - 3 Aug 2012
Externally publishedYes

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Leber's Hereditary Optic Atrophy
peripheral nervous system diseases
optics
Mitochondrial DNA
Optics
mitochondrial DNA
mutation
Genes
Mutation
Mitochondrial Genome
Substitution reactions
genes
phylogeny
genetic disorders
point mutation
Western European region
Ports and harbors
Point Mutation
Italy
France

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Achilli, A., Iommarini, L., Olivieri, A., Pala, M., Hooshiar Kashani, B., Reynier, P., ... Carelli, V. (2012). Rare primary mitochondrial DNA mutations and probable synergistic variants in leber's hereditary optic neuropathy. PLoS One, 7(8), [e42242]. https://doi.org/10.1371/journal.pone.0042242
Achilli, Alessandro ; Iommarini, Luisa ; Olivieri, Anna ; Pala, Maria ; Hooshiar Kashani, Baharak ; Reynier, Pascal ; La Morgia, Chiara ; Valentino, Maria Lucia ; Liguori, Rocco ; Pizza, Fabio ; Barboni, Piero ; Sadun, Federico ; de Negri, Anna Maria ; Zeviani, Massimo ; Dollfus, Helene ; Moulignier, Antoine ; Ducos, Ghislaine ; Orssaud, Christophe ; Bonneau, Dominique ; Procaccio, Vincent ; Leo-Kottler, Beate ; Fauser, Sascha ; Wissinger, Bernd ; Amati-Bonneau, Patrizia ; Torroni, Antonio ; Carelli, Valerio. / Rare primary mitochondrial DNA mutations and probable synergistic variants in leber's hereditary optic neuropathy. In: PLoS One. 2012 ; Vol. 7, No. 8.
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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. 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.",
author = "Alessandro Achilli and Luisa Iommarini and Anna Olivieri and Maria Pala and {Hooshiar Kashani}, Baharak and Pascal Reynier and {La Morgia}, Chiara and Valentino, {Maria Lucia} and Rocco Liguori and Fabio Pizza and Piero Barboni and Federico Sadun and {de Negri}, {Anna Maria} and Massimo Zeviani and Helene Dollfus and Antoine Moulignier and Ghislaine Ducos and Christophe Orssaud and Dominique Bonneau and Vincent Procaccio and Beate Leo-Kottler and Sascha Fauser and Bernd Wissinger and Patrizia Amati-Bonneau and Antonio Torroni and Valerio Carelli",
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Achilli, A, Iommarini, L, Olivieri, A, Pala, M, Hooshiar Kashani, B, Reynier, P, La Morgia, C, Valentino, ML, Liguori, R, Pizza, F, Barboni, P, Sadun, F, de Negri, AM, 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 2012, 'Rare primary mitochondrial DNA mutations and probable synergistic variants in leber's hereditary optic neuropathy', PLoS One, vol. 7, no. 8, e42242. https://doi.org/10.1371/journal.pone.0042242

Rare primary mitochondrial DNA mutations and probable synergistic variants in leber's hereditary optic neuropathy. / Achilli, Alessandro; Iommarini, Luisa; Olivieri, Anna; Pala, Maria; Hooshiar Kashani, Baharak; Reynier, Pascal; La Morgia, Chiara; Valentino, Maria Lucia; Liguori, Rocco; Pizza, Fabio; Barboni, Piero; Sadun, Federico; de Negri, Anna Maria; Zeviani, Massimo; Dollfus, Helene; Moulignier, Antoine; Ducos, Ghislaine; Orssaud, Christophe; Bonneau, Dominique; Procaccio, Vincent; Leo-Kottler, Beate; Fauser, Sascha; Wissinger, Bernd; Amati-Bonneau, Patrizia; Torroni, Antonio; Carelli, Valerio.

In: PLoS One, Vol. 7, No. 8, e42242, 03.08.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare primary mitochondrial DNA mutations and probable synergistic variants in leber's hereditary optic neuropathy

AU - Achilli, Alessandro

AU - Iommarini, Luisa

AU - Olivieri, Anna

AU - Pala, Maria

AU - Hooshiar Kashani, Baharak

AU - Reynier, Pascal

AU - La Morgia, Chiara

AU - Valentino, Maria Lucia

AU - Liguori, Rocco

AU - Pizza, Fabio

AU - Barboni, Piero

AU - Sadun, Federico

AU - de Negri, Anna Maria

AU - Zeviani, Massimo

AU - Dollfus, Helene

AU - Moulignier, Antoine

AU - Ducos, Ghislaine

AU - Orssaud, Christophe

AU - Bonneau, Dominique

AU - Procaccio, Vincent

AU - Leo-Kottler, Beate

AU - Fauser, Sascha

AU - Wissinger, Bernd

AU - Amati-Bonneau, Patrizia

AU - Torroni, Antonio

AU - Carelli, Valerio

PY - 2012/8/3

Y1 - 2012/8/3

N2 - 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.

AB - 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.

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