NDUFS3 – Leigh syndrome

Biallelic variants in NDUFS3 have been implicated in autosomal recessive Leigh syndrome (MONDO:0009723), a mitochondrial encephalopathy characterized by subacute necrotizing lesions in the basal ganglia and brainstem, elevated lactate, and early-onset neurodegeneration.

Inheritance is autosomal recessive, with at least four unrelated probands reported to carry biallelic NDUFS3 variants (two missense and two splice alleles) across three independent studies ([PMID:14729820]; [PMID:30140060]; [PMID:33097395]). Genetic evidence includes segregation of compound heterozygous or homozygous alleles in affected individuals, although extended pedigree data remain limited.

In a Chinese patient, targeted MitoExome sequencing identified two missense mutations in NDUFS3: c.418C>T (p.Arg140Trp) and c.595C>T (p.Arg199Trp), of which c.418C>T was novel. Patient-derived lymphoblastoid cells exhibited reduced NDUFS3 protein levels and impaired complex I assembly compared with controls ([PMID:30140060]).

A series of complex I–deficient patients screened by denaturing HPLC and sequencing revealed NDUFS3 mutations—including c.434C>T (p.Thr145Ile) and c.595C>T (p.Arg199Trp)—in individuals with late-onset Leigh syndrome and optic atrophy ([HP:0000648]) ([PMID:14729820]). More recently, two adults with mild Leigh syndrome carried biallelic splice-regulatory variants (c.419G>A (p.Arg140Gln) and c.381+6T>C), correlating with partially preserved complex I activity ([PMID:33097395]).

Functional studies demonstrate that loss of NDUFS3 recapitulates human pathology: patient cells show defective complex I assembly, and a neuron-specific Ndufs3 knockout mouse exhibits reduced complex I activity, altered brain energy metabolism, and motor deficits. Administration of metformin delayed neurological symptom onset in the mouse model without exacerbating lactic acidosis, highlighting a potential therapeutic avenue ([PMID:33148885]).

Collectively, moderate clinical validity is supported by multiple unrelated probands with recessive biallelic variants, concordant cellular and animal model data demonstrating loss-of-function mechanism, and preliminary pharmacological rescue. NDUFS3 testing should be incorporated into diagnostic panels for early-onset mitochondrial encephalopathies and informs potential metformin-based therapeutic strategies.

References

• Journal of medical genetics • 2004 • Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. PMID:14729820
• Journal of human genetics • 2018 • A Novel NDUFS3 mutation in a Chinese patient with severe Leigh syndrome. PMID:30140060
• Molecular genetics and metabolism • 2020 • Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome. PMID:33097395
• JCI insight • 2020 • Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency. PMID:33148885

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