MT-ND4 – Mitochondrial Disease

MT-ND4 encodes the NADH ubiquinone oxidoreductase subunit 4 of respiratory chain Complex I. Pathogenic variants in MT-ND4 impair oxidative phosphorylation and underlie a spectrum of mitochondrial disorders (MONDO:0044970) transmitted via maternal inheritance. Genetic screening and functional assays have consistently implicated MT-ND4 in multi-system phenotypes including myopathy, seizures and metabolic dysfunction.

Several unrelated probands harbor heteroplasmic MT-ND4 missense mutations. A novel m.11777C>A (p.Arg340Ser) variant was identified in 2 unrelated patients with Leigh syndrome and correlated with severe Complex I deficiency in cybrid assays ([PMID:16120329]). A distinct m.11240C>T (p.Leu374Phe) mutation was reported in a patient with Leigh syndrome, showing reduced ATP‐linked respiration in transmitochondrial cybrids ([PMID:27761019]). A third m.12058C>T (p.Glu433Asp) substitution was found in a patient with complex I dysfunction and severe multisystem involvement ([PMID:34089464]). These cases total 4 independent probands with MT-ND4 variants and maternal segregation in extended pedigrees.

In a cohort of 1 559 patients suspected of mitochondrial encephalomyopathies, high‐throughput screening detected MT-ND4 m.11778G>A in 1 of 373 patients with sensorineural hearing loss and in additional subjects with myopathy and seizures ([PMID:20123042]). Overall, 158 of 1 559 patients carried one of eight recurrent mtDNA mutations (10.1%) with MT-ND4 variants contributing to the phenotypic spectrum of exercise intolerance, cardiomyopathy and neurodegeneration. In 76 unrelated probands, heteroplasmy levels of A3243G and G11778A correlated with myopathy and seizure severity ([PMID:20123042]).

Functional studies demonstrate that MT-ND4 mutations disrupt Complex I assembly and activity. Allotopic expression of recoded ND4 mRNA targeted to mitochondria fully rescued growth on galactose and ATP synthesis in fibroblasts bearing the LHON-linked m.11778G>A mutation ([PMID:17518546]). In vivo delivery of mutant human ND4 via AAV to mouse retinal ganglion cells reproduced optic atrophy, reduced pattern electroretinogram amplitudes and axonal degeneration, mirroring human Leber hereditary optic neuropathy ([PMID:22773905]).

Biochemical characterization in cybrids and bacterial models confirms a haploinsufficiency mechanism: mutations at the proton‐pumping channel (e.g., R340S, L374F) and at transmembrane helices impair deamino-NADH oxidase activity and proton translocation, while assembly of Complex I remains intact in some variants ([PMID:16120329]; [PMID:35306226]). Synergistic effects with mitochondrial tRNA variants further modulate phenotypic expressivity, underscoring the complexity of genotype–phenotype correlations.

Integration of genetic and experimental data supports a ClinGen Moderate association between MT-ND4 and generic mitochondrial disease. Multiple independent probands with deleterious MT-ND4 variants, maternal segregation, recurrent allele screening and concordant functional assays substantiate diagnostic testing for ND4 mutations. Routine inclusion of MT-ND4 in mitochondrial gene panels enables precision diagnosis and informs prognostic counseling.

References

• Mitochondrion • 2003 • A novel mtDNA C11777A mutation in Leigh syndrome. PMID:16120329
• Journal of human genetics • 2017 • Novel mutation of ND4 gene identified by targeted next-generation sequencing in patient with Leigh syndrome. PMID:27761019
• Molecular biology reports • 2021 • Mitochondrial disease patients with novel ND4 12058A>C and ND1 m.3911>G variations: implications for a role in the phenotype following a bioinformatic investigation. PMID:34089464
• Mitochondrion • 2010 • Detection of eight frequently encountered point mutations in mitochondria in Chinese patients suggestive of mitochondrial encephalomyopathies. PMID:20123042
• Rejuvenation research • 2007 • Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits. PMID:17518546
• Molecular vision • 2012 • Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice. PMID:22773905

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