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 language | English |
|---|---|
| Pages (from-to) | 130-7 |
| Journal | Mitochondrion |
| Volume | 36 |
| DOIs | |
| Publication status | Published - 2017 |
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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
Incomplete penetrance in mitochondrial optic neuropathies. / Caporali, Leonardo; Maresca, Alessandra; Capristo, Mariantonietta; Del Dotto, Valentina; Tagliavini, Francesca; Valentino, Maria Lucia; La Morgia, Chiara; Carelli, Valerio.
In: Mitochondrion, Vol. 36, 2017, p. 130-7.Research output: Contribution to journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85025124749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025124749&partnerID=8YFLogxK
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
SP - 130
EP - 137
JO - Mitochondrion
JF - Mitochondrion
SN - 1567-7249
ER -