Incomplete penetrance in mitochondrial optic neuropathies

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12 Citations (Scopus)

Abstract

Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively.For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON.Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity.Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies.

Original languageEnglish
Pages (from-to)130-7
JournalMitochondrion
Volume36
DOIs
Publication statusPublished - 2017

Fingerprint

Leber's Hereditary Optic Atrophy
Optic Nerve Diseases
Penetrance
Mitochondrial DNA
Autosomal Dominant Optic Atrophy
DNA
Organelle Biogenesis
Sexism
Optic Atrophy
Optic Nerve
Proteomics
Tobacco
Estrogens
Smoking
Alcohols
Mutation

Keywords

  • Dominant optic atrophy
  • Environmental triggers
  • Genetic modifiers
  • Incomplete penetrance
  • Inherited optic neuropathies
  • Leber's Hereditary Optic Neuropathy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cell Biology

Cite this

@article{944f97d57ec842ec92ec50e52ee08d7d,
title = "Incomplete penetrance in mitochondrial optic neuropathies",
abstract = "Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively.For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON.Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity.Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies.",
keywords = "Dominant optic atrophy, Environmental triggers, Genetic modifiers, Incomplete penetrance, Inherited optic neuropathies, Leber's Hereditary Optic Neuropathy",
author = "Leonardo Caporali and Alessandra Maresca and Mariantonietta Capristo and {Del Dotto}, Valentina and Francesca Tagliavini and Valentino, {Maria Lucia} and {La Morgia}, Chiara and Valerio Carelli",
note = "Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Universit{\`a} di Bologna (Valentino Maria Lucia, La Morgia Chiara, Carelli Valerio)",
year = "2017",
doi = "10.1016/j.mito.2017.07.004",
language = "English",
volume = "36",
pages = "130--7",
journal = "Mitochondrion",
issn = "1567-7249",
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TY - JOUR

T1 - Incomplete penetrance in mitochondrial optic neuropathies

AU - Caporali, Leonardo

AU - Maresca, Alessandra

AU - Capristo, Mariantonietta

AU - Del Dotto, Valentina

AU - Tagliavini, Francesca

AU - Valentino, Maria Lucia

AU - La Morgia, Chiara

AU - Carelli, Valerio

N1 - Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Valentino Maria Lucia, La Morgia Chiara, Carelli Valerio)

PY - 2017

Y1 - 2017

N2 - Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively.For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON.Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity.Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies.

AB - Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively.For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON.Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity.Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies.

KW - Dominant optic atrophy

KW - Environmental triggers

KW - Genetic modifiers

KW - Incomplete penetrance

KW - Inherited optic neuropathies

KW - Leber's Hereditary Optic Neuropathy

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U2 - 10.1016/j.mito.2017.07.004

DO - 10.1016/j.mito.2017.07.004

M3 - Article

C2 - 28716668

AN - SCOPUS:85025124749

VL - 36

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JO - Mitochondrion

JF - Mitochondrion

SN - 1567-7249

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