Identification of a novel m.3955G > A variant in MT-ND1 associated with Leigh syndrome

Leigh syndrome (LS) is one of the most common mitochondrial diseases in children, for which at least 90 causative genes have been identified. However, many LS patients have no genetic diagnosis, indicating that more disease-related genes remain to be identified. In this study, we identified a novel variant, m.3955G > A, in mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in two unrelated LS patients, manifesting as infancy-onset frequent seizures, neurodegeneration, elevated lactate levels, and bilateral symmetrical lesions in the brainstem, basal ganglia, and thalamus. Transfer of the mutant mtDNA with m.3955G > A into cybrids disturbed the MT-ND1 expression and CI assembly, followed by remarkable mitochondrial dysfunction, reactive oxygen species production, and mitochondrial membrane potential reduction. Our findings demonstrated the pathogenicity of the novel m.3955G > A variant, and extend the spectrum of pathogenic mtDNA variants.