NDUFAF4 – Mitochondrial Complex I Deficiency

NDUFAF4 is an autosomal recessive assembly factor for mitochondrial complex I. Two siblings from a single family harbored biallelic variants—c.7G>C (p.Ala3Pro) and c.478G>T (p.Glu160Ter)—and presented with early-onset lactic acidosis and cardiomyopathy consistent with complex I deficiency (2 probands) (PMID:28853723, PMID:32949790). No additional segregation beyond the sibling pair has been described. The involvement of NDUFAF4 in complex I assembly is supported by its tight interaction with NDUFAF3 (PMID:19463981).

Functional analyses of patient fibroblasts demonstrated almost complete absence of fully assembled complex I and related supercomplexes, accompanied by altered mitochondrial morphology and reduced respiratory capacity. Lentiviral complementation with wild-type NDUFAF4 fully rescued complex I assembly and function, confirming a loss-of-function mechanism, and knockdown studies recapitulated the biochemical defect (PMID:28853723).

Although evidence is limited to a single family, concordant biochemical and cellular assays support a Limited clinical validity classification for NDUFAF4 in mitochondrial complex I deficiency. Key take-home: NDUFAF4 should be included in diagnostic panels for autosomal recessive complex I deficiency.

References

• Mitochondrion • 2020 • Complex I deficiency, due to NDUFAF4 mutations, causes severe mitochondrial dysfunction and is associated to early death and dysmorphia. PMID:32949790
• European journal of human genetics : EJHG • 2017 • NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect. PMID:28853723
• 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

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