NDUFS1 – Mitochondrial Disease

NDUFS1 encodes the 75-kDa iron–sulfur subunit of mitochondrial complex I, and biallelic loss-of-function or hypomorphic variants cause autosomal recessive mitochondrial disease characterized by multisystem energy failure. Complex I deficiency is a leading cause of mitochondrial disorders, often presenting in infancy with hypotonia, lactic acidosis, neurodevelopmental regression, leukoencephalopathy, and Leigh-like syndromes. Genetic testing by dual genomic sequencing and targeted gene panels has improved diagnostic yield in pediatric cohorts, identifying NDUFS1 among the nuclear‐encoded complex I subunits disrupted in mitochondrial disease.

A total of ≥11 unrelated probands from at least eight families have been reported with biallelic NDUFS1 variants (PMID:11349233, PMID:21203893, PMID:25615419, PMID:20382551). The inheritance mode is autosomal recessive, with segregation demonstrated in consanguineous sibships (two affected siblings segregating the homozygous c.1783A>G (p.Thr595Ala) variant) (PMID:21203893).

The variant spectrum includes missense substitutions (e.g., p.Thr595Ala), nonsense alleles (p.Arg557Ter), frameshift indels (e.g., p.Ile225SerfsTer), splice-site changes, and small in-frame deletions, consistent with loss of enzyme function. A representative pathogenic change is c.1783A>G (p.Thr595Ala) (PMID:21203893).

Functional studies in patient fibroblasts and model organisms show markedly reduced complex I assembly and residual activity, accumulation of reactive oxygen species, and impaired mitochondrial membrane potential. Insertional mutagenesis in Neurospora crassa and galactose-challenge assays in patient cells recapitulate the biochemical phenotype, confirming the deleterious effect of NDUFS1 deficiency (PMID:21203893, PMID:16478720).

Cellular rescue-assays restoring wild-type NDUFS1 expression recover complex I enzyme activity and normalize oxidative stress markers, providing direct causality evidence and supporting potential therapeutic strategies targeting mitochondrial function (PMID:21458341).

Collectively, these genetic and experimental data establish a strong gene–disease relationship between NDUFS1 and autosomal recessive mitochondrial disease. Additional reports continue to expand the allelic and phenotypic spectrum beyond the ClinGen scoring cap.

Key Take-home: Biallelic NDUFS1 variants lead to deficient complex I activity underlying a broad mitochondrial disease phenotype, and functional assays enable definitive molecular diagnosis and inform potential rescue approaches.

References

• American journal of human genetics • 2001 • Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. PMID:11349233
• Neurogenetics • 2011 • Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1. PMID:21203893
• Mitochondrion • 2015 • Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. PMID:25615419
• Molecular genetics and metabolism • 2010 • Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. PMID:20382551
• The Journal of biological chemistry • 2006 • Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I. PMID:16478720
• Molecular genetics and metabolism • 2011 • Cellular rescue-assay aids verification of causative DNA-variants in mitochondrial complex I deficiency. PMID:21458341

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