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NDUFS6
NADH:ubiquinone oxidoreductase subunit S6
NDUFS6 is located on the short (p) arm of chromosome 5, at band 5p15.33. Arm ratio per GRCh38 - banding schematic.
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Overview
NDUFS6 encodes NADH:ubiquinone oxidoreductase subunit S6, a component of mitochondrial complex I (NADH dehydrogenase). Complex I is the entry point for electrons into the respiratory chain, the sequence of protein complexes that generates most of the cell's chemical energy in the form of ATP. The NDUFS6 protein is one of numerous subunits that together form this large enzyme assembly.
Mitochondria are often called the cell's powerhouses because they produce the energy needed for nearly all cellular activities. When NDUFS6 variants impair complex I function, cells may struggle to generate sufficient energy, particularly affecting organs with high metabolic demands such as the brain, muscles, and heart. The gene is located on chromosome 5 and produces a relatively small protein of 124 amino acids.
What the gene does
The NDUFS6 protein is a structural and functional component of mitochondrial complex I, which catalyses the transfer of electrons from NADH to ubiquinone whilst simultaneously pumping protons across the inner mitochondrial membrane. This proton gradient drives ATP synthesis, the universal energy currency of cells. Complex I contains more than 40 different protein subunits, and NDUFS6 contributes to the stable assembly and proper function of this multi-protein machinery.
Within complex I, NDUFS6 is thought to help maintain the structural integrity of the enzyme and may participate in coordinating electron transfer reactions. The protein localises to the mitochondrial matrix, where it integrates into the membrane-embedded portion of complex I. Efficient complex I activity is essential for cellular respiration, particularly in tissues with high energy requirements. When complex I function is compromised, cells may experience oxidative stress and energy depletion, leading to cellular dysfunction and tissue damage over time.
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Chromosome location
NDUFS6 is located on the short arm of chromosome 5 at position 15.33 (5p15.33). This chromosomal region is near the telomere, the protective cap at the end of the chromosome. The gene is relatively compact, reflecting the small size of its protein product.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The NDUFS6 protein comprises 124 amino acids and functions as an integral component of the much larger complex I assembly. Its compact size suggests it serves a specialised structural or catalytic role within the multi-subunit enzyme rather than containing multiple independent functional domains.
Key variants
Pathogenic variants in NDUFS6 are associated with mitochondrial respiratory chain disorders, specifically those involving complex I deficiency. These variants typically reduce or eliminate the protein's ability to contribute to normal complex I assembly or function. The inheritance pattern can vary depending on the specific variant and clinical context, and genetic testing may identify changes classified as pathogenic, likely pathogenic, or variants of uncertain significance.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.109G>T | p.Glu37Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.242del | p.Glu81fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 9 |
c.309+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency |
c.309+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 9 |
c.309+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 9 |
c.309+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 9 |
c.320_323del | p.Thr107fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 9 |
c.32_33dup | p.Asn12Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 9 |
c.343T>C | p.Cys115Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency |
c.67dup | p.Leu23fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in NDUFS6 have been linked to mitochondrial disorders characterised by complex I deficiency. These conditions can present with a broad spectrum of clinical features, often affecting multiple organ systems. Common manifestations may include neurological problems such as developmental delay, seizures, and movement disorders, alongside metabolic disturbances. Some individuals experience muscle weakness, exercise intolerance, or cardiac involvement. The severity and specific combination of symptoms can vary considerably between affected individuals, even within the same family.
No disease links recorded for this gene in our reference set.
UK clinical status
NDUFS6 appears on several NHS Genomic Medicine Service gene panels used for diagnosing inherited conditions in the UK. These include the Mitochondrial disorders panel, the Mitochondrial disorder with complex I deficiency panel (R353), and the Likely inborn error of metabolism panel (R98). The gene is also part of panels for Hereditary neuropathy or pain disorder (R78), Possible mitochondrial disorder - nuclear genes (R63), and Undiagnosed metabolic disorders. Inclusion on these panels with green classification indicates there is robust evidence supporting the gene's role in the relevant conditions, and testing may be offered through NHS clinical pathways when a patient's symptoms suggest a possible mitochondrial or metabolic disorder.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the NDUFS6 gene do?
NDUFS6 provides instructions for making a protein subunit of complex I, the first enzyme in the mitochondrial respiratory chain. Complex I helps convert nutrients into cellular energy (ATP), and the NDUFS6 protein contributes to the assembly and function of this large enzyme complex.
How are NDUFS6 variants inherited?
Inheritance patterns for NDUFS6-related conditions can vary. Because the gene is located in the cell nucleus rather than in mitochondrial DNA, variants are typically inherited in an autosomal recessive manner, meaning an individual would need to inherit a pathogenic variant from both parents to be affected.
Can NDUFS6 variants be detected through NHS testing?
Yes, NDUFS6 is included on multiple NHS Genomic Medicine Service gene panels for mitochondrial and metabolic disorders. Testing may be offered when a patient's clinical features suggest complex I deficiency or another mitochondrial condition, following assessment by a specialist.