Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Mitochondrial complex I deficiency is a common inborn error of oxidative phosphorylation characterized by neuromuscular and multisystem involvement. The MT-ND1 gene encodes the NADH dehydrogenase subunit 1, a core component of complex I. Pathogenic variants in MT-ND1 impair electron transfer from NADH to ubiquinone, leading to reduced ATP production and lactic acidosis. Maternal inheritance of MT-ND1 mutations underlies diverse clinical phenotypes ranging from isolated myopathy to Leigh syndrome and MELAS. Here, we summarize the genetic and functional evidence supporting a strong association between MT-ND1 and MONDO_0100133 (mitochondrial complex I deficiency).
Multiple independent case reports have identified MT-ND1 variants in patients with isolated complex I deficiency. An intragenic inversion maintained the reading frame but altered three conserved amino acids in a patient with mitochondrial myopathy and isolated complex I defect (1 proband; PMID:10775530). Two de novo heteroplasmic missense changes (m.3890G>A p.Arg195Gln and m.3481G>A p.Glu59Lys) were found in infants with Leigh syndrome and complex I deficiency (2 probands; PMID:18504678). A homoplasmic m.4087A>G (p.Thr261Ala) variant segregated with recurrent myoglobinuria in a single family (7 carriers; PMID:26108648).
Further series and case reports expand the spectrum of MT-ND1 pathogenic variants. A novel m.3928G>C (p.Val208Leu) was identified de novo in Leigh syndrome with infantile spasms (1 proband; PMID:24063851). Two patients with MELAS features carried m.3959G>A and m.3995A>G missense changes, each reducing ND1 stability (2 probands; PMID:23834081). A de novo frameshift m.3571_3572insC caused complex I deficiency in a MELAS patient, confirmed by load-dependent functional assays (1 proband; PMID:36717040).
The variant spectrum in MT-ND1 includes missense substitutions, small inversions, and frameshift insertions, often heteroplasmic and occasionally homoplasmic. Maternal segregation and de novo occurrences underscore varied inheritance patterns. None of these variants are found in population databases, and most occur at conserved residues within transmembrane helices critical for ubiquinone binding.
Functional studies consistently demonstrate severe complex I defects. Blue-Native PAGE and immunoblotting show reduced assembly of holo–complex I in patient-derived cybrids and muscle (PMID:32158465, PMID:34311469). Oxygen consumption rate and ATP synthesis assays reveal marked bioenergetic impairment, while ROS production is elevated. In vitro rescue of complex I activity by expression of wild-type ND1 corroborates pathogenicity.
No substantial conflicting evidence has been reported; one study in psychiatric disease failed to show functional impairment for a T3394C MT-ND1 variant, suggesting variant-specific effects (PMID:17320116). Taken together, the genetic and experimental concordance across multiple independent reports supports a Strong clinical validity score. MT-ND1 sequencing should be included in diagnostic panels for complex I deficiency, and variant confirmation by functional assays is recommended.
Key Take-home: MT-ND1 pathogenic variants are robustly associated with mitochondrial complex I deficiency, manifesting with variable neuromuscular and neurodegenerative phenotypes, and supported by consistent functional defects.
Gene–Disease AssociationStrong≥8 unrelated probands with MT-ND1 variants presenting with mitochondrial complex I deficiency, familial segregation, and concordant functional data Genetic EvidenceStrongMultiple independent MT-ND1 variants in seven unrelated patients and one family demonstrating maternal inheritance and complex I defects Functional EvidenceModerateConsistent defects in complex I assembly and activity across cell models, Blue-Native PAGE, oxygen consumption, and rescue assays |