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NDUFAF3 (HGNC:29918) encodes an assembly factor essential for mitochondrial respiratory chain complex I. Biallelic variants in NDUFAF3 cause autosomal recessive mitochondrial disease (NDUFAF3, mitochondrial disease). Seven unrelated probands have been described: five familial cases in three pedigrees (PMID:19463981), one Leigh syndrome patient (PMID:27986404), and one 10-year-old with progressive dystonia and exercise intolerance (PMID:37572574). Inheritance is autosomal recessive with compound heterozygous or homozygous variants. Segregation in five families supports co-segregation of biallelic alleles with disease. The clinical spectrum ranges from fatal neonatal onset to later childhood movement disorders. These findings underpin inclusion of NDUFAF3 in diagnostic panels for complex I deficiencies.
Variant spectrum includes four missense changes, two loss-of-function alleles (one frameshift p.Asp61Ter, one start-loss p.Met1Thr), and one splice-site variant. Notably, the homozygous missense variant c.494C>T (p.Ala165Val) was identified in a Leigh syndrome patient (PMID:27986404). In a compound heterozygous dystonia case, a novel splice-site change co-occurred with a second missense allele (PMID:37572574). Population data show absence of biallelic carriers. These findings provide strong genetic evidence for pathogenicity under a loss-of-function mechanism.
Homozygosity mapping in consanguineous families and parental segregation by Sanger sequencing confirmed trans inheritance and co-segregation in five pedigrees (PMID:19463981, PMID:37572574). No unaffected siblings carry biallelic variants. Segregation scores are consistent with autosomal recessive inheritance.
Functional assays in patient fibroblasts demonstrated a 30–50% residual complex I activity reduction by spectrophotometry (PMID:37572574) and restoration of complex I assembly upon NDUFAF3-GFP complementation (PMID:19463981). Complexome profiling revealed severe depletion of NDUFAF3 and complex I subunits with accumulation of early membrane-arm subassemblies associated with the MCIA complex (PMID:37572574). These data confirm NDUFAF3’s role in early complex I biogenesis.
No conflicting reports dispute NDUFAF3’s role in mitochondrial disease. The combined genetic and experimental evidence meets ClinGen criteria for Strong gene–disease association, Strong genetic evidence, and Moderate functional evidence. Additional cohort studies could further refine genotype–phenotype correlations. NDUFAF3 should be included in gene panels for suspected complex I defects, enabling timely diagnosis and potential therapeutic exploration.
Key take-home: Biallelic NDUFAF3 variants cause autosomal recessive mitochondrial disease with variable severity, from neonatal fatal presentations to childhood dystonia, supported by robust genetic and functional validation.
Gene–Disease AssociationStrongSeven probands from five unrelated families with consistent segregation and concordant functional data Genetic EvidenceStrongMultiple biallelic variants (missense, LoF, splice) in seven probands with segregation support Functional EvidenceModerateFibroblast assays and complexome profiling confirm loss-of-function and role in complex I assembly |