NDUFV2 – Mitochondrial Complex I Deficiency

NDUFV2 encodes the 24 kDa core subunit of mitochondrial respiratory chain Complex I. Biallelic loss-of-function variants in NDUFV2 underlie an autosomal recessive mitochondrial complex I deficiency presenting in infancy or early childhood with encephalopathy, axial hypotonia and variable cardiomyopathy. Affected individuals have demonstrated markedly reduced Complex I enzyme activity in muscle and fibroblasts and elevated lactate/pyruvate ratios, consistent with mitochondrial respiratory chain dysfunction.

Genetic Evidence

Seven unrelated probands from four families have been reported with autosomal recessive NDUFV2 variants (7 probands) ([PMID:26008862]; [PMID:34405929]). In one kindred, two siblings carried compound heterozygous splice (c.300+2T>A) and frameshift (c.669_670insG (p.Ser224ValfsTer3)) variants, with complete segregation in both affected siblings and obligate carriers ([PMID:26008862]). A second consanguineous family had three of five siblings homozygous for the canonical splice donor variant. Two additional unrelated cases were solved by multi-omics: one with c.427C>T (p.Arg143Ter) in trans with a novel heterozygous exon deletion revealed by genome sequencing and RNA-seq ([PMID:34405929]). The spectrum includes splice, frameshift and nonsense variants consistent with a loss-of-function mechanism.

Functional Evidence

Patient tissues exhibit deficient Complex I enzymatic activity in muscle biopsies and cultured fibroblasts, confirming pathogenicity of the splice and truncating alleles ([PMID:26008862]). RNA sequencing demonstrated aberrant exon skipping for the intronic delGTAA allele, and genome sequencing identified an Alu insertion-mediated exon deletion in one case, with rescue of Complex I assembly upon complementation in patient fibroblasts ([PMID:34405929]). These functional assays concordantly support a null mechanism.

Conflicting Evidence

No studies have reported pathogenic NDUFV2 variants in isolation without Complex I deficiency. A synonymous substitution (c.201A>T) observed in controls was shown to be functionally neutral and unlikely to contribute to disease ([PMID:16142472]).

Integration and Clinical Utility

Collectively, the genetic and experimental data satisfy ClinGen criteria for a Strong gene–disease association. Biallelic loss-of-function NDUFV2 variants cause early-onset mitochondrial Complex I deficiency with consistent biochemical and molecular findings. Sequencing of NDUFV2 should be incorporated into diagnostic panels for pediatric mitochondrial disorders, enabling accurate genetic counselling and the potential for targeted metabolic therapies.

Key Take-Home: Pathogenic biallelic NDUFV2 variants cause autosomal recessive mitochondrial Complex I deficiency; genetic testing and enzymatic assays are diagnostic cornerstones.

References

• European journal of paediatric neurology • 2015 • Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome. PMID:26008862
• Human mutation • 2021 • Genome sequencing and RNA-seq analyses of mitochondrial complex I deficiency revealed Alu insertion-mediated deletion in NDUFV2. PMID:34405929
• Journal of molecular medicine (Berlin, Germany) • 2005 • Sequence analysis of nuclear genes encoding functionally important complex I subunits in children with encephalomyopathy. PMID:16142472

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