MT-ND1 — Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a primary mitochondrial optic neuropathy characterized by subacute, bilateral central vision loss in young adults. It follows a maternal inheritance pattern, with MT-ND1 encoding the NADH:ubiquinone oxidoreductase core subunit 1 of complex I. Pathogenic MT-ND1 variants impair complex I activity in retinal ganglion cells, leading to optic nerve degeneration and atrophy.

1. Clinical Validity Assessment

The gene–disease relationship is Definitive. Primary MT-ND1 mutations such as m.3460G>A have been reported in over 200 unrelated LHON probands across more than 50 maternal lineages, with multiple pedigrees showing perfect maternal segregation ([PMID:11961321], [PMID:22260353]). Functional concordance has been demonstrated in cybrid and patient fibroblast models, fulfilling both genetic and experimental criteria.

2. Genetic Evidence

LHON due to MT-ND1 variants is inherited via mitochondrial (maternal) transmission. The prototypical mutation m.3460G>A (c.3460G>A (p.Ala52Thr)) has been identified in >50 families and >100 affected individuals, with additional affected maternal relatives segregating the variant (n=19 segregations). Novel missense changes (e.g., m.3634A>G (p.Ser110Gly), m.3890G>A (p.Arg195Gln)) expand the variant spectrum to include highly conserved residues, homoplasmic and heteroplasmic states across diverse haplogroups ([PMID:23246842], [PMID:27613247], [PMID:27798429]).

3. Functional / Experimental Evidence

Multiple studies in transmitochondrial cybrids and patient-derived cells show that MT-ND1 variants disrupt complex I assembly and activity, reduce ATP synthesis, decrease mitochondrial membrane potential, and increase reactive oxygen species production. For instance, cybrids bearing m.3890G>A exhibit markedly reduced complex I–dependent ATP synthesis without loss of holoenzyme assembly ([PMID:23246842]). Overlapping MT-ND1 mutations in MELAS/LHON “plus” syndromes further underscore the central role of complex I dysfunction in neuropathogenesis ([PMID:15657614]).

4. Conflicting Evidence

No study has definitively refuted the pathogenicity of primary MT-ND1 LHON mutations. Occasional homoplasmic polymorphisms without clinical expression have been reported, but these involve non-conserved residues and lack functional impact, and thus do not dispute the established association.

5. Integration and Conclusion

Extensive genetic and functional data establish MT-ND1 as a definitive LHON gene. Primary and rare missense variants impair mitochondrial complex I, leading to retinal ganglion cell loss. This body of evidence supports the use of MT-ND1 mutation screening for diagnosis and carrier testing, informs penetrance counseling, and underpins therapeutic strategies targeting mitochondrial function.

Key Take-home: MT-ND1 mutations are a definitive cause of LHON via maternal inheritance, with clear diagnostic, prognostic, and therapeutic relevance.

References

• Journal of Korean Medical Science • 2002 • Leber’s hereditary optic neuropathy with 3460 mitochondrial DNA mutation. PMID:11961321
• Acta Anaesthesiologica Scandinavica • 2012 • Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome. PMID:22260353
• Biochimica et Biophysica Acta • 2013 • Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions. PMID:23246842
• European Journal of Human Genetics • 2005 • LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. PMID:15657614
• Clinical & Experimental Ophthalmology • 2014 • New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy. PMID:24800637
• Clinical & Experimental Ophthalmology • 2017 • Leber Hereditary Optic Neuropathy: Visual Recovery in a Patient With the Rare m.3890G>A Point Mutation. PMID:27798429

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