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MT-ND5 encodes the ND5 subunit of mitochondrial respiratory chain complex I, essential for oxidative phosphorylation in human cells. Pathogenic variants in MT-ND5 disrupt complex I assembly or function, leading to a spectrum of mitochondrial disease phenotypes ranging from Leigh syndrome to multisystem mitochondrial encephalomyopathy. The maternal inheritance pattern and recurrence of key mutations across unrelated patients support a definitive gene–disease relationship.
Maternal inheritance of MT-ND5 variants has been documented in multiple pedigrees and sporadic cases, with at least 12 unrelated probands presenting with complex I deficiency and diverse clinical features (e.g., hypertrophic cardiomyopathy, lactic acidosis, encephalopathy) across five published reports (PMID:14520659; PMID:17106447; PMID:11938446) and case series (PMID:25681084; PMID:35677009). No clear autosomal or X-linked modes have been observed, consistent with mitochondrial inheritance.
Genetic evidence includes pathogenic missense mutations such as m.13513G>A (p.Asp393Asn) in MT-ND5 identified in infants with Leigh syndrome and cardiomyopathy, often with heteroplasmy levels >30% in muscle (PMID:25681084; PMID:36104228). A novel T12706C (p.Leu236Pro) variant has been reported in a patient with Leigh neuropathology and complex I deficiency (PMID:11938446). Family studies show maternal transmission without recombination, although clear segregation of phenotype is limited by heteroplasmy and variable expressivity. Reported additional affected relatives remain low (affected_relatives: 0).
Functional studies in patient-derived cybrid models and biochemical assays demonstrate that MT-ND5 mutations impair complex I assembly and activity. The m.13513G>A mutation at ∼45% heteroplasmy reduces fully assembled complex I by ~50% and lowers its enzymatic activity in muscle and fibroblasts (PMID:14520659). The T12706C variant alters a conserved transmembrane residue, correlating with defective NADH:ubiquinone oxidoreductase activity and decreased ATP generation (PMID:17317336). Animal modeling using optimized mitochondrial base editors recapitulated the mt-Nd5 A12784G equivalent, yielding vision loss and heart rate abnormalities in mice, further validating pathogenicity mechanisms (PMID:39843744).
No studies to date have refuted the association of MT-ND5 with mitochondrial disease, and no significant conflicting evidence has been reported. Variable heteroplasmy and tissue-specific expression explain the phenotypic heterogeneity rather than discordant findings.
In summary, MT-ND5 pathogenic variants cause maternal‐inherited mitochondrial disease through disrupted complex I function, yielding neurologic, cardiac, and metabolic phenotypes. The definitive clinical validity, strong genetic evidence, and robust functional concordance support MT-ND5 testing in suspected mitochondrial disease, informing diagnosis, management, and genetic counseling.
Key Take-Home: MT-ND5 variants are definitively implicated in complex I–related mitochondrial disease, with maternal transmission and multisystem impact warranting targeted genetic testing.
Gene–Disease AssociationDefinitive≥12 unrelated probands with MT-ND5 variants demonstrating complex I deficiency and broad multisystem phenotypes, maternal inheritance, multiple functional studies showing complex I impairment Genetic EvidenceStrong12 probands with pathogenic MT-ND5 variants across multiple case reports reached the ClinGen genetic evidence cap Functional EvidenceStrongConcordant cybrid, enzymatic, and animal model studies demonstrate MT-ND5 mutation–driven complex I assembly/activity defects and phenotypic recapitulation |