NDUFV2 – Leigh syndrome

NDUFV2 encodes the 24 kDa NADH-ubiquinone oxidoreductase core subunit V2 of mitochondrial complex I and is required for oxidative phosphorylation. Biallelic loss-of-function variants in NDUFV2 cause autosomal recessive Leigh syndrome, a progressive neurodegenerative disorder characterized by axial hypotonia, encephalopathy, and brain atrophy.

In the initial report, two siblings presented with hypertrophic cardiomyopathy and brain atrophy due to complex I deficiency. Whole-exome sequencing identified compound heterozygous mutations in NDUFV2: the known splice donor variant c.300+2T>A and a novel frameshift c.669_670insG (p.Ser224ValfsTer3), leading to early protein truncation and absent enzyme activity in muscle and fibroblasts ([PMID:26008862]).

Screening of ten additional unrelated probands revealed homozygosity for the c.300+2T>A splice mutation in a consanguineous family in which three of five siblings were affected, all exhibiting Leigh syndrome without cardiac involvement (3 affected relatives) ([PMID:26008862]).

Functional studies demonstrated significantly reduced complex I enzymatic activity in patient muscle and elevated lactate/pyruvate ratio in fibroblasts, consistent with a loss-of-function mechanism. The concordance between genetic findings and biochemical assays supports pathogenicity of NDUFV2 truncating variants.

No conflicting evidence has been reported to date. Collectively, the genetic and functional data establish a strong gene–disease association between NDUFV2 and Leigh syndrome.

Key Take-home: Biallelic NDUFV2 truncating variants reliably diagnose autosomal recessive Leigh syndrome and should be included in mitochondrial disease gene panels.

References

• European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society • 2015 • Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome. PMID:26008862

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