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Incomplete penetrance in mitochondrial optic neuropathies
- Source :
- Mitochondrion. 36:130-137
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Mitochondrial DNA
Dominant optic atrophy
genetic structures
Penetrance
Optic Atrophy, Hereditary, Leber
Biology
DNA, Mitochondrial
Genetic modifier
Optic neuropathy
03 medical and health sciences
0302 clinical medicine
Optic Atrophy, Autosomal Dominant
Optic Nerve Diseases
medicine
Humans
Molecular Biology
Incomplete penetrance
Genetics
Mechanism (biology)
Leber's hereditary optic neuropathy
Environmental Exposure
Cell Biology
medicine.disease
eye diseases
Mitochondria
030104 developmental biology
Mitochondrial biogenesis
Molecular Medicine
Environmental trigger
Mitochondrial optic neuropathies
Inherited optic neuropathie
030217 neurology & neurosurgery
Leber's Hereditary Optic Neuropathy
Human mitochondrial DNA haplogroup
Subjects
Details
- ISSN :
- 15677249
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Mitochondrion
- Accession number :
- edsair.doi.dedup.....fbf4c3baf40fbf5cfe8747140240d0bc