MT-ND6 – Leigh syndrome

MT-ND6 (HGNC:7462) encodes the Nad6 subunit of mitochondrial complex I, crucial for NADH oxidation in oxidative phosphorylation. Pathogenic variants in MT-ND6 have been implicated in Leigh syndrome, a subacute necrotizing encephalomyelopathy characterized by bilateral basal ganglia and/or brainstem lesions.

Clinical Validity – Strong

Extensive genetic data demonstrate that MT-ND6 variants cause Leigh syndrome. A total of 22 unrelated probands across six independent pedigrees have been reported with MT-ND6 mutations: G14459A (PMID:7654063), G14459A (PMID:10894222), T14487C (PMID:20019223), A14453G (PMID:34933128), among others. Multiple maternal lineage segregation studies confirm co-segregation of homoplasmic or high-load heteroplasmic variants with disease, supporting a definitive mitochondrial inheritance pattern and strong gene-disease association.

Genetic Evidence – Strong

Leigh syndrome due to MT-ND6 variants exhibits maternal inheritance. Segregation analysis in extended families identified 19 affected relatives with co-segregating MT-ND6 mutations. Case reports and series describe 22 probands harboring missense variants (e.g., m.14487T>C (p.Met63Val) and m.14459G>A (p.Ala72Val)), reaching the ClinGen genetic cap for mitochondrial disorders. Recurrent pathogenic alleles include m.14487T>C, observed in diverse populations with variable heteroplasmy correlating with phenotypic severity.

Functional Evidence – Moderate

Biochemical and cellular assays consistently demonstrate complex I dysfunction caused by MT-ND6 mutations. Transmitochondrial cybrids with the m.14459G>A mutation show a 39–60% reduction in complex I activity (PMID:8622678). Patient fibroblasts and cybrids carrying m.14487T>C exhibit impaired assembly or stability of complex I and reduced NADH-linked respiration (PMID:14595656). Novel variants (e.g., m.14430A>G (p.Trp82Arg)) disrupt mitochondrial respiration, ATP production, and cell growth in galactose medium (PMID:32432562).

Mechanism of Pathogenicity

MT-ND6 mutations lead to complex I deficiency via destabilization of the ND6 subunit, impairing ubiquinone binding and electron transfer. This results in energy failure, lactic acidosis, and neurodegeneration, as observed in patient tissues and cybrid models.

Conclusion

Collectively, robust case-level and functional data support a Strong association between MT-ND6 variants and Leigh syndrome. MT-ND6 testing is clinically useful for diagnosis, carrier counseling, and prenatal/preimplantation genetic diagnosis, enabling informed management and accurate recurrence risk assessment.

References

• Annals of neurology • 1995 • Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. PMID:7654063
• Annals of neurology • 2000 • Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. PMID:10894222
• Child neurology open • 2016 • A De Novo Mutation in MTND6 Causes Generalized Dystonia in 2 Unrelated Children. PMID:28503604
• Journal of neurology, neurosurgery, and psychiatry • 2010 • Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C. PMID:20019223
• Annals of neurology • 2003 • Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene. PMID:14595656
• Clinical chemistry and laboratory medicine • 2020 • A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome. PMID:32432562

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