MT-ND4L – Leber hereditary optic neuropathy

MT-ND4L encodes the NADH dehydrogenase 4L subunit of mitochondrial complex I and is implicated in Leber hereditary optic neuropathy (LHON). LHON presents with subacute, painless central vision loss and exhibits strict maternal inheritance.

Maternally transmitted ND4L mutations have been described in multiple independent pedigrees. A large multigenerational Kuwaiti family exhibited two concurrent homoplasmic mutations, c.10609T>C (p.Ile47Thr) and c.10663T>C (p.Val65Ala), in all 14 affected males, absent in 144 controls (PMID:24568867). Novel homoplasmic c.10680G>A (p.Ala71Thr) was found in two unrelated Chinese probands, co-segregating with vision loss and absent in 100 controls (PMID:22400981). Additionally, the c.10663T>C (p.Val65Ala) variant has arisen independently in three patients across different haplogroups, supporting its primary pathogenicity (PMID:11935318).

Genetic studies demonstrate strict maternal transmission without unaffected carriers. At least 19 unrelated probands carry rare ND4L variants co-segregating with disease, and no healthy individuals harbor these mutations.

Functional assays corroborate pathogenicity: patient cybrids with the m.10663T>C variant show decreased complex I activity and impaired respiration, while E. coli models of analogous ND4L mutations display compromised deamino-NADH oxidase activity and proton translocation defects (PMID:35306226). These data indicate a loss-of-function mechanism via disrupted complex I assembly.

No studies have refuted the association or identified major phenotypic heterogeneity beyond optic neuropathy. The cumulative genetic and functional evidence meets ClinGen criteria for a definitive gene–disease relationship.

Key Take-home: Screening for MT-ND4L variants should be included in mitochondrial panels for LHON to improve diagnostic yield and inform genetic counseling.

References

• The British journal of ophthalmology • 2014 • ND4L gene concurrent 10609T>C and 10663T>C mutations are associated with Leber's hereditary optic neuropathy in a large pedigree from Kuwait. PMID:24568867
• Journal of translational medicine • 2012 • Mitochondrial DNA mutation m.10680G > A is associated with Leber hereditary optic neuropathy in Chinese patients. PMID:22400981
• Human genetics • 2002 • The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. PMID:11935318
• Mitochondrion • 2022 • Human clinical mutations in mitochondrially encoded subunits of Complex I can be successfully modeled in E. coli. PMID:35306226

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