NDUFS1 – Mitochondrial Complex I Deficiency

NDUFS1 encodes the 75-kDa iron–sulfur subunit of mitochondrial complex I, an essential component of the respiratory chain. Autosomal recessive biallelic pathogenic variants in NDUFS1 cause mitochondrial complex I deficiency (MONDO:0100133), a heterogeneous disorder of energy metabolism.

Biallelic NDUFS1 variants have been reported in fourteen unrelated probands: three in a cohort of 36 patients (PMID:11349233); two of 23 children with isolated complex I deficiency (PMID:15576045); one case with mild cavitating leukoencephalopathy (PMID:24952175); three individuals with low residual complex I activity (PMID:20382551); two inbred siblings with progressive cavitating leukoencephalopathy (PMID:21203893); and three patients from three families with variable phenotypes (PMID:25615419). Variants include missense, nonsense, and frameshift alleles in homozygous or compound heterozygous configurations, with a recurrent missense c.755A>G (p.Asp252Gly) segregating in multiple families.

Segregation analysis in consanguineous and multiplex families demonstrates full concordance with autosomal recessive inheritance, including two affected siblings segregating homozygous variants.

Functional studies on patient fibroblasts and muscle tissue show impaired assembly and reduced activity of complex I; NDUFS1 deficiency leads to accumulation of reactive oxygen species, decreased mitochondrial potential, and rescue of complex I function upon wild-type cDNA complementation (PMID:16478720; PMID:21458341). A Neurospora crassa model of the NDUFS1 mutation recapitulates the mitochondrial dysfunction seen in patients (PMID:21203893).

Clinically, NDUFS1-related complex I deficiency presents with early onset hypotonia (HP:0001252), ataxia (HP:0001251), psychomotor retardation (HP:0001253), and diffuse leukoencephalopathy (HP:0002352), with variable progression from mild to severe phenotypes.

Integration of genetic and experimental data supports a loss-of-function mechanism through haploinsufficiency of the Fe-S subunit. Routine sequencing of NDUFS1 is recommended in patients with complex I deficiency, and functional assays provide diagnostic confirmation.

Key take-home: Biallelic NDUFS1 variants are a well-supported cause of autosomal recessive mitochondrial complex I deficiency with distinctive leukoencephalopathy and should be included in diagnostic gene panels.

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
• Biochimica et biophysica acta • 2004 • Clinical and molecular findings in children with complex I deficiency. PMID:15576045
• Neurogenetics • 2014 • A homozygous mutation in the NDUFS1 gene presents with a mild cavitating leukoencephalopathy. PMID:24952175
• Molecular genetics and metabolism • 2010 • Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. PMID:20382551
• 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
• 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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