ArticlePLoS genetics2018
Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber's hereditary optic neuropathy.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 59 citations in OpenAlex.
- Mitochondrial complex I deficiency-associated diseases and models.Cellular and molecular life sciences : CMLS · 2026Review
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- The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.Heliyon · 2025Article
- Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants.Frontiers in neurology · 2025Article
- Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia.BMC genomics · 2024Article
- Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.Cell reports. Medicine · 2024Article
- Novel JAG1 variants leading to Alagille syndrome in two Chinese cases.Scientific reports · 2024Article
- RecessiveJournal of medical genetics · 2023Article
- The Italian reappraisal of the most frequent genetic defects in hereditary optic neuropathies and the global top 10.Brain : a journal of neurology · 2023Article
- APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.Nature communications · 2023Article
- Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts.Journal of experimental & clinical cancer research : CR · 2023Article
- OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.Communications biology · 2023Article
- Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.EXCLI journal · 2023Article
- Comparative mitogenomic and evolutionary analysis of Lycaenidae (Insecta: Lepidoptera): Potential association with high-altitude adaptation.Frontiers in genetics · 2023Article
- Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Toxic and nutritional factors trigger Leber hereditary optic neuropathy due to a mitochondrial tRNA mutation.Clinical genetics · 2022Article
- Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.Cell reports · 2022Article
- Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder.Frontiers in genetics · 2022Article
- Mitochondrial DNA variation in Parkinson's disease: Analysis of "out-of-place" population variants as a risk factor.Frontiers in aging neuroscience · 2022Article
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25 authors at 8 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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