NDUFS6 – Mitochondrial Disease

NDUFS6 encodes an accessory subunit of mitochondrial complex I, essential for electron transport and ATP synthesis. Bi-allelic loss-of-function or splice-altering variants in NDUFS6 disrupt complex I assembly and activity, leading to a spectrum of mitochondrial disease phenotypes (NDUFS6; Mitochondrial Disease). The diagnostic yield of next-generation sequencing in Mendelian mitochondrial disorders has been demonstrated in a cohort of 59 patients, where NDUFS6 was one of seven genes with novel variants in the mitochondrial group (PMID:33629572).

Inheritance of NDUFS6-related mitochondrial disease is autosomal recessive. Five probands with bi-allelic NDUFS6 variants have been reported: one individual with homozygous c.343T>C (p.Cys115Arg) and c.309+5G>A (PMID:38217609) and four affected individuals from three unrelated families homozygous for c.309+5G>A (PMID:38459834). Segregation analysis confirmed co-segregation of c.309+5G>A with disease in all affected relatives (4 individuals) across these families.

Variants observed include missense changes (e.g., c.343T>C (p.Cys115Arg)), splice-site substitutions (c.309+5G>A), and likely null alleles. The recurrent c.309+5G>A variant exhibits a hypomorphic splicing effect, producing aberrant transcripts with negligible canonical mRNA but without overt complex I instability in patient cells (PMID:38459834).

Patient-derived leukocytes from the proband harboring c.309+5G>A and p.Cys115Arg showed loss of NDUFS6 protein and secondary reduction of assembly factors NDUFA12, NDUFS4, and NDUFV1, confirming a loss-of-function mechanism without global mtDNA depletion or elevation of GDF15 (PMID:38217609).

In vivo models corroborate pathogenicity: Ndufs6(gt/gt) mice exhibit tissue-specific splicing rescue but develop marked cardiac complex I deficiency with biventricular enlargement and early mortality (PMID:22474353), and partial knockdown induces renal impairment with albuminuria, fibrosis, and reduced mitochondrial ATP production (PMID:23320803).

Together, these data support a mechanism of autosomal recessive loss of NDUFS6 leading to mitochondrial complex I deficiency and a variable clinical spectrum ranging from neonatal cardiomyopathy to later-onset neuropathy and optic atrophy. Additional unidentified families and functional studies may further expand the phenotype. Key take-home: bi-allelic NDUFS6 variants cause clinically actionable mitochondrial disease amenable to genetic diagnosis and functional confirmation.

References

• Journal of pediatric endocrinology & metabolism • 2021 • The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum. PMID:33629572
• Journal of neuromuscular diseases • 2024 • A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy. PMID:38217609
• Genetics in medicine : official journal of the American College of Medical Genetics • 2024 • Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders. PMID:38459834
• Proceedings of the National Academy of Sciences of the United States of America • 2012 • Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy. PMID:22474353
• Antioxidants & redox signaling • 2013 • Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease. PMID:23320803

Evidence Based Scoring (AI generated)