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NDUFS7 – Mitochondrial Complex I Deficiency

NDUFS7 encodes a core subunit of mitochondrial respiratory chain complex I. Autosomal recessive loss-of-function variants in NDUFS7 cause mitochondrial complex I deficiency (NDUFS7; mitochondrial complex I deficiency).

Genetic evidence is limited. In one family, two siblings with Leigh syndrome–like complex I deficiency harbored a homozygous intronic splice variant c.16+5>A segregating with disease (PMID:39894241) in trans with a presumed second allele. An independent patient with progressive leukoencephalopathy carried a heterozygous complex rearrangement in a single NDUFS7 allele, suggesting unconventional inheritance (PMID:15576045). No additional unrelated cases or extensive segregation studies have been reported.

Functional studies support a pathogenic mechanism of haploinsufficiency leading to complex I assembly defects. Patient-derived fibroblasts with c.16+5>A showed isolated complex I assembly deficiency by Blue Native PAGE (PMID:39894241). In HEK293T cells, NDUFS7 knockout induced elevated apoptosis and oxidative stress that was rescued by upregulation of SLC7A11-mediated cystine import, demonstrating a protective pathway against NDUFS7 deficiency–induced cell death (PMID:38823363).

Key Take-home: While genetic evidence remains limited to a small number of families, concordant functional data confirm that NDUFS7 deficiency impairs complex I assembly, supporting its clinical utility in diagnosing mitochondrial complex I deficiency.

References

  • 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
  • Biochemical and biophysical research communications • 2024 • SLC7A11-mediated cystine import protects against NDUFS7 deficiency-induced cell death in HEK293T cells. PMID:38823363
  • Biochimica et biophysica acta • 2004 • Clinical and molecular findings in children with complex I deficiency. PMID:15576045

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three probands across two studies: two siblings with biallelic intronic NDUFS7 c.16+5>A variant segregating in one family ([PMID:39894241]), and a single patient with heterozygous NDUFS7 rearrangement ([PMID:15576045]).

Genetic Evidence

Limited

Identification of a biallelic intronic splice variant in two affected siblings and one heterozygous allele in an independent patient, without extensive segregation.

Functional Evidence

Moderate

Patient fibroblasts with c.16+5>A showed complex I assembly defect by Blue Native PAGE ([PMID:39894241]), and SLC7A11-mediated cystine import protected NDUFS7-deficient HEK293T cells from apoptosis ([PMID:38823363]).