Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy

Leonardo Caporali, Luisa Iommarini, Chiara La Morgia, Anna Olivieri, Alessandro Achilli, Alessandra Maresca, Maria Lucia Valentino, Mariantonietta Capristo, Francesca Tagliavini, Valentina Del Dotto, Claudia Zanna, Rocco Liguori, Piero Barboni, Michele Carbonelli, Veronica Cocetta, Monica Montopoli, Andrea Martinuzzi, Giovanna Cenacchi, Giuseppe De Michele, Francesco TestaAnna Nesti, Francesca Simonelli, Anna Maria Porcelli, Antonio Torroni, Valerio Carelli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numbere1007210
JournalPLoS Genetics
Volume14
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

Fingerprint

Leber's Hereditary Optic Atrophy
penetrance
peripheral nervous system diseases
Penetrance
optics
Mitochondrial DNA
mitochondrial DNA
NADH dehydrogenase (ubiquinone)
cybrids
mutation
Mothers
maternal lineage
Electron Transport Complex I
Mutation
oxidative phosphorylation
Oxidative Phosphorylation
translocation
Haplotypes
gold
protons

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

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.

In: PLoS Genetics, Vol. 14, No. 2, e1007210, 01.02.2018.

Research output: Contribution to journalArticle

Caporali, L, Iommarini, L, La Morgia, C, Olivieri, A, Achilli, A, Maresca, A, Valentino, ML, Capristo, M, Tagliavini, F, Del Dotto, V, Zanna, C, Liguori, R, Barboni, P, Carbonelli, M, Cocetta, V, Montopoli, M, Martinuzzi, A, Cenacchi, G, De Michele, G, Testa, F, Nesti, A, Simonelli, F, Porcelli, AM, Torroni, A & Carelli, V 2018, 'Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy', PLoS Genetics, vol. 14, no. 2, e1007210. https://doi.org/10.1371/journal.pgen.1007210
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. / Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy. In: PLoS Genetics. 2018 ; Vol. 14, No. 2.
@article{5d1fca386ee94267ba4ac44203197ba4,
title = "Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy",
abstract = "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.",
author = "Leonardo Caporali and Luisa Iommarini and {La Morgia}, Chiara and Anna Olivieri and Alessandro Achilli and Alessandra Maresca and Valentino, {Maria Lucia} and Mariantonietta Capristo and Francesca Tagliavini and {Del Dotto}, Valentina and Claudia Zanna and Rocco Liguori and Piero Barboni and Michele Carbonelli and Veronica Cocetta and Monica Montopoli and Andrea Martinuzzi and Giovanna Cenacchi and {De Michele}, Giuseppe and Francesco Testa and Anna Nesti and Francesca Simonelli and Porcelli, {Anna Maria} and Antonio Torroni and Valerio Carelli",
year = "2018",
month = "2",
day = "1",
doi = "10.1371/journal.pgen.1007210",
language = "English",
volume = "14",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy

AU - Caporali, Leonardo

AU - Iommarini, Luisa

AU - La Morgia, Chiara

AU - Olivieri, Anna

AU - Achilli, Alessandro

AU - Maresca, Alessandra

AU - Valentino, Maria Lucia

AU - Capristo, Mariantonietta

AU - Tagliavini, Francesca

AU - Del Dotto, Valentina

AU - Zanna, Claudia

AU - Liguori, Rocco

AU - Barboni, Piero

AU - Carbonelli, Michele

AU - Cocetta, Veronica

AU - Montopoli, Monica

AU - Martinuzzi, Andrea

AU - Cenacchi, Giovanna

AU - De Michele, Giuseppe

AU - Testa, Francesco

AU - Nesti, Anna

AU - Simonelli, Francesca

AU - Porcelli, Anna Maria

AU - Torroni, Antonio

AU - Carelli, Valerio

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85043303250&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043303250&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1007210

DO - 10.1371/journal.pgen.1007210

M3 - Article

AN - SCOPUS:85043303250

VL - 14

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 2

M1 - e1007210

ER -