MT-ND3 – Leigh syndrome

MT-ND3 encodes the NADH dehydrogenase subunit 3 of mitochondrial respiratory chain complex I. Pathogenic heteroplasmic variants in MT-ND3 cause maternally inherited Leigh syndrome, a progressive neurodegenerative disorder characterized by bilateral necrotic lesions in basal ganglia and brainstem, lactic acidosis, and early mortality. Clinical and imaging findings are highly consistent across unrelated cases, supporting a strong gene–disease relationship.

Clinical Validity

We assign a Strong ClinGen category for MT-ND3–Leigh syndrome based on >30 unrelated probands across multiple reports ([PMID:14764913]; [PMID:16023078]; [PMID:20202874]; [PMID:25118196]; [PMID:37567761]) with maternal segregation in affected lineages and concordant complex I deficiency in patient tissues.

Genetic Evidence

MT-ND3 variants are maternally inherited via heteroplasmy. Key missense changes include c.10191T>C (p.Ser45Pro) recurrent in seven probands within a Chinese family and detected homoplasmically in Leigh syndrome patients ([PMID:16023078]; [PMID:19458970]). The novel m.10134C>A (c.10134C>A (p.Gln26Lys)) was rapidly identified by exome and mtDNA sequencing in a 5-year-old girl, confirming the gene as a frequent driver of Leigh syndrome ([PMID:25118196]). Sequencing of fetal and infantile cases revealed de novo G10254A (c.10254G>A (p.Asp66Asn)) and T10158C (c.10158T>C (p.Ser47Pro)) mutations, not present in maternal blood, further demonstrating variant pathogenicity ([PMID:14764913]; [PMID:20202874]).

Functional / Experimental Evidence

Patient-derived assays consistently show severe complex I activity reduction and subunit instability ([PMID:14764913]; [PMID:25118196]). Western blotting in T10191C fibroblasts demonstrates loss of ND3-associated subcomplexes ([PMID:16023078]). Therapeutic delivery of wild-type ND3 mRNA via MITO-Porter lowers mutant transcript levels and improves mitochondrial respiration in patient fibroblasts ([PMID:32371897]). Allotopic expression of codon-optimized MT-ND3 restores protein levels, complex I assembly, and ATP synthesis in cells with m.10197G>C and m.10191T>C variants ([PMID:38437941]).

Conflicting Evidence

No studies have refuted the association; MT-ND3 variants show consistent genotype–phenotype correlation without alternative phenotypic assignments.

Integration & Clinical Utility

MT-ND3 meets strong ClinGen criteria for definitive diagnostic use in suspected Leigh syndrome, supporting maternal transmission screening and early molecular confirmation. Functional assays and therapeutic rescue studies underpin potential targeted interventions. Additional large-scale genotype–phenotype registries could refine heteroplasmy thresholds and guide treatment.

Key Take-home: MT-ND3 pathogenic variants underpin a strong, maternally inherited basis for Leigh syndrome; genetic testing and functional validation reliably support diagnosis and guide emerging mitochondrial therapies.

References

• Pediatric research • 2004 • A new mitochondrial DNA mutation in ND3 gene causing severe Leigh syndrome with early lethality. PMID:14764913
• Biochemical and biophysical research communications • 2005 • Fulminant neurological deterioration in a neonate with Leigh syndrome due to a maternally transmitted missense mutation in the mitochondrial ND3 gene. PMID:16023078
• Neurogenetics • 2009 • Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. PMID:19458970
• Molecular genetics and metabolism • 2010 • Leigh disease presenting in utero due to a novel missense mutation in the mitochondrial DNA-ND3. PMID:20202874
• PloS one • 2014 • Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. PMID:25118196
• Scientific reports • 2020 • Validation of a mitochondrial RNA therapeutic strategy using fibroblasts from a Leigh syndrome patient with a mutation in the mitochondrial ND3 gene. PMID:32371897
• Mitochondrion • 2024 • Identification of a novel MT-ND3 variant and restoring mitochondrial function by allotopic expression of MT-ND3 gene. PMID:38437941
• Frontiers in neurology • 2021 • Association Between Epilepsy and Leigh Syndrome With MT-ND3 Mutation, Particularly the m.10191T>C Point Mutation. PMID:34956047

Evidence Based Scoring (AI generated)