NDUFS7 – Leigh syndrome

Leigh syndrome is a severe, progressive neurodegenerative disorder characterized by bilateral basal ganglia lesions, lactic acidosis, hypotonia, and psychomotor regression. Pathogenic variants in NDUFS7, encoding the PSST subunit of mitochondrial complex I, have been identified in autosomal recessive Leigh syndrome. Initial reports described a homozygous missense variant c.364G>A (p.Val122Met) in two siblings with neuropathologically confirmed complex I deficiency (PMID:10360771). A recent study identified a deep intronic splice site variant c.16+5>A segregating in another sibship with progressive basal ganglia and midbrain involvement (PMID:39894241).

The inheritance is autosomal recessive, with segregation demonstrated in two independent families (four affected sibs total) and absent in healthy relatives. Variant spectrum in NDUFS7 includes recurrent missense alleles (p.Val122Met) and intronic splice defects that impair mRNA processing. Functional studies in the yeast model Yarrowia lipolytica reconstructed the human p.Val122Met substitution, revealing ~50% reduction in complex I activity and altered ubiquinone kinetics (PMID:11004438). In vivo rescue assays in a Drosophila ND-20 knockdown model showed that wildtype canine NDUFS7 delays lethality, whereas the p.Val179Met allele does not, confirming loss-of-function (PMID:38316835).

No conflicting human reports have refuted the association, and functional concordance across species supports haploinsufficiency as the mechanism. Together, genetic segregation, variant characterization, and experimental modeling provide strong clinical validity and a moderate to high level of genetic and functional evidence. Clinical testing for NDUFS7 variants is recommended in patients with suspected Leigh syndrome or isolated complex I deficiency.

Key Take-home: NDUFS7 loss-of-function mutations cause autosomal recessive Leigh syndrome; genetic testing and functional assays guide diagnosis and potential therapeutic strategies.

References

• Annals of neurology • 1999 • Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I. PMID:10360771
• Biochimica et biophysica acta • 2000 • Application of the obligate aerobic yeast Yarrowia lipolytica as a eucaryotic model to analyse Leigh syndrome mutations in the complex I core subunits PSST and TYKY. PMID:11004438
• Scientific reports • 2024 • NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model. PMID:38316835
• Mitochondrion • 2025 • Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings. PMID:39894241

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