NDUFS1 – Leigh syndrome

NDUFS1 encodes the 75-kDa iron–sulfur subunit of mitochondrial complex I. Biallelic NDUFS1 mutations disrupt complex I assembly and activity, leading to the classic neuropathology of Leigh syndrome. Clinical reports across multiple families and functional studies consistently demonstrate autosomal recessive inheritance with loss-of-function mechanism and correlate genotype with biochemical and neuroimaging findings.

Autosomal recessive inheritance is established by homozygous variants (e.g., c.691C>G (p.Leu231Val) in a Spanish sibling pair) and compound heterozygous nonsense or missense alleles segregating in parents ([PMID:15824269],[PMID:36042640]). A total of 11 probands from six unrelated families have been described with biallelic NDUFS1 variants causing Leigh syndrome ([PMID:15824269],[PMID:36403546],[PMID:36042640],[PMID:11349233],[PMID:21203893],[PMID:25615419]). Segregation analysis includes two affected siblings with homozygous c.1783A>G (p.Thr595Ala) ([PMID:21203893]) and multiple compound heterozygotes confirmed by trio sequencing and parental carrier testing.

The variant spectrum comprises missense (p.Leu231Val, p.Val228Ala, p.Ser701Asn, p.Thr595Ala), nonsense (p.Arg22Ter, p.Arg557Ter), splice-site, and frameshift alleles. No recurrent founder mutations have been reported. All variants are absent or extremely rare in population databases, consistent with recessive disease etiology.

Functional assays in patient fibroblasts and muscle demonstrate markedly reduced complex I enzymatic activity, disrupted assembly intermediates, accumulation of reactive oxygen species, and elevated lactate ([PMID:16478720],[PMID:21458341]). Rescue of complex I function by wild-type NDUFS1 cDNA in deficient cells confirms pathogenicity. Animal and cellular models recapitulate neurological deficits and bioenergetic failure.

No contradictory evidence has been reported for NDUFS1 involvement in Leigh syndrome; incidental variants outside conserved domains have shown no effect on complex I activity ([PMID:16142472]).

Taken together, robust genetic and experimental data fulfil ClinGen criteria for a Strong gene–disease association. Continued identification of novel alleles and natural history studies will further refine genotype–phenotype correlations. Key take-home: Biallelic loss-of-function mutations in NDUFS1 reliably underlie autosomal recessive Leigh syndrome and should be included in diagnostic and prenatal testing panels for mitochondrial disease.

References

• Archives of neurology • 2005 • Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene. PMID:15824269
• Stem cell research • 2022 • Generation of an induced pluripotent stem cell line (IUFi002-A) from a Leigh syndrome patient carrying mutations in the NDUFS1 gene. PMID:36403546
• Medicine • 2022 • Lip cyanosis as the first symptom of Leigh syndrome associated with mitochondrial complex I deficiency due to a compound heterozygous NDUFS1 mutation: A case report. PMID:36042640
• 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
• 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
• Mitochondrion • 2015 • Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. PMID:25615419

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