NDUFS6 – Mitochondrial Complex I Deficiency

NDUFS6 encodes an accessory subunit of mitochondrial NADH dehydrogenase (complex I). Biallelic NDUFS6 variants have been identified in unrelated patients presenting with severe neonatal mitochondrial complex I deficiency, characterized by early-onset lactic acidosis, pulmonary arterial hypertension, and pneumonia. Genetic complementation and biochemical analyses in patient-derived cells demonstrated markedly reduced NDUFS6 expression and complex I assembly defects supporting a loss-of-function mechanism.

Autosomal recessive inheritance is established by homozygous or compound heterozygous variants in affected neonates. In one cohort, two unrelated patients harbored homozygous splice (c.132+1G>C) and deletion alleles, confirmed by homozygosity mapping and functional complementation in fibroblasts ((PMID:15372108)). A separate Chinese Hani neonate presented with a novel homozygous missense variant c.344G>T (p.Cys115Phe), correlating with rapid postnatal deterioration ((PMID:35801790)).

Segregation data are limited, with no additional affected relatives reported. The variant spectrum includes canonical splice-site mutations (e.g., c.132+1G>C), multiple early truncating alleles (c.109G>T (p.Glu37Ter), c.32_33dup (p.Asn12Ter), c.46G>T (p.Glu16Ter), c.186+2T>A), and missense changes (c.344G>T (p.Cys115Phe)). No recurrent or founder alleles have been described to date.

Functional studies in an Ndufs6 gene-trap mouse model recapitulate key features of human complex I deficiency. Ndufs6(gt/gt) mice exhibit near-complete loss of Ndufs6 in the heart, impaired ATP synthesis, myocardial fibrosis, and biventricular enlargement, resulting in progressive cardiac failure ((PMID:22474353)). Tissue-specific splicing generates partial rescue in noncardiac tissues, mirroring variable CI activity across organs.

Collectively, genetic and experimental evidence support haploinsufficiency of NDUFS6 leading to defective complex I assembly and function. No conflicting reports have disputed the association with mitochondrial complex I deficiency.

Key Take-home: Biallelic loss-of-function variants in NDUFS6 cause autosomal recessive, lethal neonatal mitochondrial complex I deficiency, with strong genetic and in vivo functional evidence to inform molecular diagnosis and therapeutic research.

References

• NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. The Journal of Clinical Investigation | 2004 PMID:15372108
• Case report: novel mutations of NDUFS6 and NHLRC2 genes potentially cause the quick postnatal death of a Chinese Hani minority neonate with mitochondrial complex I deficiency and FINCA syndrome. Medicine | 2022 PMID:35801790
• Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy. Proceedings of the National Academy of Sciences | 2012 PMID:22474353

Evidence Based Scoring (AI generated)