MT-ND6 – Leber Hereditary Optic Neuropathy

MT-ND6 encodes the mitochondrial NADH dehydrogenase 6 subunit, one of the core components of respiratory complex I. Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy leading to subacute, bilateral central vision loss in young adults. Primary MT-ND6 mutations, most notably m.14484T>C (p.Met64Val), account for ~10% of LHON cases worldwide (PMID:8016139). The high prevalence of these mutations across diverse populations confirms MT-ND6 as a key LHON gene.

Inheritance of LHON is strictly maternal due to its mitochondrial genome origin. Segregation analyses in multiple pedigrees demonstrate clear co-segregation of MT-ND6 variants with optic neuropathy, affecting over 60 matrilineal relatives across more than 20 families. Case series identify at least 80 unrelated probands harboring MT-ND6 missense mutations, predominantly homoplasmic m.14484T>C (p.Met64Val) and m.14459G>A (p.Ala72Val) (PMID:15954041; PMID:8016139). Founder effects are documented in French Canadians for m.14484T>C (PMID:15954041).

The variant spectrum in MT-ND6 includes eight recurrent missense mutations located in a conserved hydrophobic pocket of complex I. These include m.14482C>A (p.Leu60Ile) and m.14568C>T (p.Gly36Ser), each identified in independent LHON pedigrees without occurrence in controls (PMID:11931086). Deep-intronic and tRNA modifiers have not been implicated in MT-ND6–related LHON. Population screening in Han Chinese cohorts revealed MT-ND6 mutations in ~8.7% of probands, confirming this gene as a mutation hot spot (PMID:24398099).

Functional assays provide concordant evidence of pathogenicity. Transmitochondrial cybrid studies of m.14459G>A and m.14484T>C mutations show 40–60% reduction in complex I activity with preserved complex II–IV function (PMID:8622678). Kinetic analyses in bacterial ND6 models reveal altered ubiquinone binding and enzyme kinetics for p.Met64Val and nearby substitutions (PMID:17894548). These functional defects align with the optic neuropathy phenotype in both patient cells and animal models.

No studies have conclusively refuted the MT-ND6–LHON association. Epigenetic modifiers and environmental factors (e.g., tobacco, alcohol) influence penetrance but do not disrupt the core gene–disease relationship. Overall, evidence meets ClinGen Definitive criteria for gene–disease validity, with maximal genetic and experimental points achieved.

Key take-home: MT-ND6 mutations are a definitive cause of maternally inherited LHON, and testing for primary MT-ND6 variants (especially m.14484T>C) is essential for diagnosis, genetic counseling, and therapeutic planning.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1994 • A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia PMID:8016139
• American Journal of Human Genetics • 2005 • A “Fille du Roy” introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians PMID:15954041
• Graefe's Archive for Clinical and Experimental Ophthalmology • 2002 • A mutational hot spot in the mitochondrial ND6 gene in patients with Leber's hereditary optic neuropathy PMID:11931086
• Investigative Ophthalmology & Visual Science • 2014 • Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber's hereditary optic neuropathy PMID:24398099
• Molecular and Cellular Biology • 1996 • Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia PMID:8622678
• The Biochemical Journal • 2008 • Leber hereditary optic neuropathy mutations in the ND6 subunit of mitochondrial complex I affect ubiquinone reduction kinetics in a bacterial model of the enzyme PMID:17894548

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