MT-ND3 – Mitochondrial Complex I Deficiency

MT-ND3 encodes the NADH dehydrogenase 3 subunit of respiratory Complex I, an essential component of the mitochondrial oxidative phosphorylation system. Pathogenic variants in MT-ND3 disrupt electron transport, leading to impaired ATP production and a spectrum of clinical presentations collectively termed mitochondrial Complex I deficiency. This disorder manifests primarily with early-onset neurodegeneration, although onset and severity vary with tissue heteroplasmy and variant type.

Genetic evidence includes at least 10 unrelated probands harboring heteroplasmic MT-ND3 variants across five independent reports ([PMID:27742419]). Case descriptions span patients with the classic T10158C mutation to novel m.10197G>C and m.10191G>C missense changes, as well as the recently identified m.10134C>A (c.10134C>A (p.Gln26Lys)) variant. Most patients present with Leigh syndrome or MELAS-like features, including early rapid neurological decline and epilepsy.

Transmission follows a maternal mitochondrial inheritance pattern with variable tissue heteroplasmy. Segregation data are limited by sporadic occurrence and low-level heteroplasmy in unaffected maternal carriers, with no large multi-generational pedigrees reported to date.

The variant spectrum comprises predominantly missense changes affecting conserved ND3 residues with reported homoplasmic and heteroplasmic loads. Recurrent mutations include T10158C and m.10197G>A, observed in multiple unrelated individuals, without clear evidence of a founder effect. Reported phenotypes span epilepsia partialis continua (HP:0001250), optic atrophy (HP:0000648), and exercise intolerance (HP:0003546).

Functional studies demonstrate consistent Complex I enzyme deficiency in patient tissues and fibroblasts, with Western blot and spectrophotometric assays confirming reduced ND3 protein levels and activity. Rescue experiments using allotopic expression of codon-optimized MT-ND3 in patient cells restored Complex I assembly and ATP synthesis ([PMID:38437941]), while E. coli models of human ND3 mutations recapitulate enzyme defects, supporting pathogenicity.

Together, these data support a moderate ClinGen classification for MT-ND3 and mitochondrial Complex I deficiency based on multiple unrelated probands and robust functional concordance. Further large-scale segregation and natural history studies may elevate this association. Key take-home: MT-ND3 sequencing should be included in the diagnostic work-up of early-onset neurodegenerative mitochondrial disorders to inform prognosis and potential rescue strategies.

References

• Brain & development • 2017 • Complex I deficiency related to T10158C mutation ND3 gene: A further definition of the clinical spectrum. PMID:27742419
• PloS one • 2014 • Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. PMID:25118196
• The neurologist • 2016 • Mitochondrial Encephalopathy and Optic Neuropathy Due to m.10158 MT-ND3 Complex I Mutation Presenting in an Adult Patient: Case Report and Review of the Literature. PMID:27348141
• Journal of the neurological sciences • 2019 • Clinical and neuroimaging features of the m.10197G>A mtDNA mutation: New case reports and expansion of the phenotype variability. PMID:30776730
• Mitochondrion • 2024 • Identification of a novel MT-ND3 variant and restoring mitochondrial function by allotopic expression of MT-ND3 gene. PMID:38437941

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