» Articles » PMID: 28716668

Incomplete Penetrance in Mitochondrial Optic Neuropathies

Overview
Journal Mitochondrion
Specialty Cell Biology
Date 2017 Jul 19
PMID 28716668
Citations 30
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Leber's hereditary optic neuropathy like disease in variant m.8969G>A.

de Muijnck C, van Schooneveld M, Plomp A, Rodenburg R, van Genderen M, Boon C Am J Ophthalmol Case Rep. 2024; 34:102070.

PMID: 38756953 PMC: 11096717. DOI: 10.1016/j.ajoc.2024.102070.


Identification and characterization of a new pathologic mutation in a large Leber hereditary optic neuropathy pedigree.

Emperador S, Habbane M, Lopez-Gallardo E, Del Rio A, Llobet L, Mateo J Orphanet J Rare Dis. 2024; 19(1):148.

PMID: 38582886 PMC: 10999093. DOI: 10.1186/s13023-024-03165-2.


Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.

Aleo S, Del Dotto V, Romagnoli M, Fiorini C, Capirossi G, Peron C Cell Rep Med. 2024; 5(2):101383.

PMID: 38272025 PMC: 10897523. DOI: 10.1016/j.xcrm.2023.101383.


Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.

Chen C, Guan M J Biomed Sci. 2023; 30(1):82.

PMID: 37737178 PMC: 10515435. DOI: 10.1186/s12929-023-00967-7.


Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis.

Atamena D, Gurram V, Petsophonsakul P, Khosrobakhsh F, Arrazola M, Botella M Front Mol Neurosci. 2023; 16:1241222.

PMID: 37736113 PMC: 10510408. DOI: 10.3389/fnmol.2023.1241222.