NDUFS4 – Mitochondrial Complex I Deficiency

Mitochondrial complex I deficiency presents with early‐onset encephalopathy, lactic acidosis, and movement disorders, notably Leigh syndrome. Complex I comprises 43 subunits, 38 of which are nuclear encoded; NDUFS4 encodes an 18‐kDa accessory subunit critical for holoenzyme assembly. Affected individuals typically exhibit basal ganglia lesions on MRI, hypotonia, dystonia, and fatal lactic acidosis within infancy.

Initial genetic evidence emerged from homozygosity mapping in an inbred multiplex family with complex I deficiency, identifying a homozygous splice‐acceptor mutation c.99-1G>A in NDUFS4 that segregated with disease ([PMID:12616398]). Subsequent targeted exome and BN-PAGE studies described multiple patients harboring autosomal recessive loss‐of‐function variants, including frameshifts c.291del (p.Lys96_Trp97insTer) and c.472_476dup (p.Tyr160fs), in over 22 unrelated probands with Leigh syndrome ([PMID:22326555]; [PMID:27079373]). Uniparental isodisomy revealed a novel intronic splicing variant c.350+5G>A in a non-consanguineous patient, confirming complete homozygosity and phenotypic correlation in a one-year-old girl with encephalopathy and lactic acidosis ([PMID:33093004]).

The variant spectrum in NDUFS4 is dominated by splice‐site and frameshift alleles predicted to truncate the protein. Recurrent mutations such as c.291del (p.Lys96_Trp97insTer) and c.472_476dup (p.Tyr160fs) have been reported in multiple families, including a North‐African founder allele ([PMID:22326555]). No deep‐intronic or large structural variants have been definitively implicated, and missense changes are rare and generally non‐pathogenic.

Functional assays in patient fibroblasts consistently demonstrate failure to assemble the mature complex I holoenzyme on blue native PAGE ([PMID:22326555]). Nonsense-mediated decay studies show that premature termination codons in exon 1 abrogate mRNA surveillance and alter the balance of splice variants ([PMID:15038602]). These data support a loss-of-function mechanism via haploinsufficiency.

The Ndufs4 knockout mouse recapitulates key clinical features, including retinal ganglion cell loss, neurodevelopmental defects, and activation of innate immune pathways preceding neurodegeneration ([PMID:25652399]). Hepatic bioenergetic studies reveal an ~86 % reduction in complex I activity and compensatory reliance on complex II, with widespread metabolic perturbations in glucose, amino acid, and nucleotide pathways ([PMID:40498175]). Together with rescue experiments using dibutyryl-cAMP in cellular models, these findings highlight potential therapeutic avenues.

In aggregate, NDUFS4 meets ClinGen “Strong” criteria for association with autosomal recessive mitochondrial complex I deficiency (Leigh syndrome). Truncating and splice-site mutations segregate in multiple multiplex and unrelated families, and functional studies across patient cells and animal models consistently demonstrate pathogenic complex I assembly defects. Key take-home: NDUFS4 loss-of-function mutations are reliably diagnostic for early-onset Leigh syndrome and warrant inclusion in prenatal and diagnostic gene panels.

References

• Human genetics • 2003 • Genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families with respiratory chain complex I deficiency allows rapid identification of a novel nonsense mutation (IVS1nt -1) in the NDUFS4 gene in Leigh syndrome. PMID:12616398
• Biochimica et biophysica acta • 2012 • A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome. PMID:22326555
• Mitochondrion • 2016 • Ndufs4 related Leigh syndrome: A case report and review of the literature. PMID:27079373
• Molecular genetics and metabolism • 2020 • Uniparental isodisomy as a cause of mitochondrial complex I respiratory chain disorder due to a novel splicing NDUFS4 mutation. PMID:33093004
• Neurochemical research • 2004 • Respiratory complex I in brain development and genetic disease. PMID:15038602
• Human molecular genetics • 2015 • Mitochondrial complex I deficiency leads to inflammation and retinal ganglion cell death in the Ndufs4 mouse. PMID:25652399
• Metabolomics : Official journal of the Metabolomic Society • 2025 • Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model. PMID:40498175

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