NDUFAF3 – Mitochondrial Complex I Deficiency

NDUFAF3 encodes a mitochondrial complex I assembly factor that is essential for proper oxidative phosphorylation. biallelic variants in NDUFAF3 have been implicated in autosomal recessive mitochondrial complex I deficiency (mitochondrial complex I deficiency), a disorder characterized by early-onset lactic acidosis, neurodegeneration, and multi-system involvement.

Genetic evidence for this association comes from five probands across three unrelated families identified through homozygosity mapping and targeted sequencing, all harboring deleterious NDUFAF3 variants including the frameshift c.180_181insT (p.Asp61Ter) (PMID:19463981). These variants segregate with disease under an autosomal recessive model, and variant spectrum comprises both loss-of-function and missense alleles.

Functional complementation studies using NDUFAF3-GFP baculovirus in patient fibroblasts demonstrate restoration of complex I assembly and activity, confirming the pathogenicity of identified alleles (PMID:19463981).

Subsequent fibroblast assays in a patient with a novel homozygous missense variant (c.494C>T (p.Ala165Val)) expanded the phenotype to include Leigh syndrome, further linking NDUFAF3 dysfunction to neurodegenerative mitochondrial disease (PMID:27986404).

Together, these data provide strong genetic and moderate functional evidence for NDUFAF3 as a causative gene in autosomal recessive mitochondrial complex I deficiency. Comprehensive variant detection in NDUFAF3 is recommended in patients with early-onset complex I deficiency or Leigh syndrome.

References

• American journal of human genetics • 2009 • Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. PMID:19463981
• Molecular genetics and metabolism • 2017 • Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome. PMID:27986404

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