MT-ND2 – Mitochondrial Complex I Deficiency

MT-ND2 encodes the mitochondrially-encoded NADH dehydrogenase subunit 2, a core component of respiratory complex I. Pathogenic variants in MT-ND2 compromise electron transport, leading to the heterogeneous clinical presentation of mitochondrial complex I deficiency (MONDO:0100133), which manifests with neuromuscular, ocular and multisystem involvement.

Genetic Evidence

A prospective cohort of 13 patients with complex I deficiency demonstrated frequent visual impairment, ptosis and optic atrophy in those harboring mitochondrial gene defects (13 probands) (PMID:20346082). In a retrospective study of 133 Chinese children, mtDNA sequencing in 62 patients identified MT-ND2 variants in 32 individuals (51.6%) including the recurrent 4833A>G change in 11.3% of cases (PMID:24502327). A single-patient report described a heteroplasmic c.4831G>A (p.Gly121Asp) substitution in MT-ND2, present at 95% in muscle and correlating with isolated complex I deficiency (PMID:28070494). These data support multiple unrelated probands with MT-ND2 mutations in complex I deficiency.

Inheritance and Segregation

MT-ND2 variants follow maternal transmission. There is limited formal segregation data in complex I deficiency pedigrees for MT-ND2, and no additional affected relatives have been documented beyond case reports.

Functional Evidence

Cybrid studies of the MT-ND2 C4936T (p.Thr156Ile) mutation revealed a 60% reduction in oxygen consumption and 75% decrease in reactive oxygen species production, with aberrant cell growth phenotypes under differing metabolic conditions (PMID:22925728). Modeling of human MT-ND2 clinical variants in E. coli showed concordant reductions in deamino-NADH oxidase and proton translocation activities, confirming impaired complex I function (PMID:35306226).

Integration and Clinical Utility

Collectively, cohort and case-level studies establish that MT-ND2 missense mutations are recurrent in complex I deficiency, and functional assays consistently demonstrate loss of complex I activity. There are no reported studies refuting these associations. The genetic and mechanistic concordance supports a Moderate level of clinical validity under ClinGen criteria.

Key Take-home: MT-ND2 pathogenic variants cause mitochondrial complex I deficiency via impaired electron transport, warranting mtDNA sequencing in suspected cases to inform diagnosis and management.

References

• Acta ophthalmologica • 2012 • Visual function, ocular motility and ocular characteristics in patients with mitochondrial complex I deficiency. PMID:20346082
• Clinical genetics • 2015 • A study of 133 Chinese children with mitochondrial respiratory chain complex I deficiency. PMID:24502327
• Molecular genetics and metabolism reports • 2017 • Pure myopathy with enlarged mitochondria associated to a new mutation in MTND2 gene. PMID:28070494
• FASEB journal • 2012 • Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions. PMID:22925728
• 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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