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NDUFAF6
NADH:ubiquinone oxidoreductase complex assembly factor 6
NDUFAF6 is located on the long (q) arm of chromosome 8, at band 8q22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
NDUFAF6 is located on chromosome 8 and provides instructions for making a protein that helps build complex I of the mitochondrial respiratory chain. Complex I is the largest enzyme complex in mitochondria and catalyses the first step in oxidative phosphorylation, the process by which cells convert nutrients into usable energy in the form of ATP.
The NDUFAF6 protein acts as an assembly factor, ensuring that the many individual subunits of complex I come together correctly during the construction of the complete enzyme. Without functional NDUFAF6, complex I assembly is impaired, leading to reduced enzyme activity and compromised cellular energy production. This assembly defect particularly affects tissues with high energy demands, such as the brain and muscles, resulting in mitochondrial disease.
What the gene does
The NDUFAF6 protein functions specifically during the assembly of mitochondrial complex I, a process that requires the coordinated addition of multiple protein subunits into a functional enzyme. NDUFAF6 assists in the maturation and incorporation of these subunits, acting as a molecular chaperone that guides proper protein folding and positioning within the developing complex.
Research suggests that NDUFAF6 participates in intermediate assembly stages, helping to stabilise nascent complex I modules as they are constructed. The protein is thought to interact transiently with complex I subunits during assembly but does not become part of the final mature enzyme. When NDUFAF6 is absent or non-functional, partially assembled complex I intermediates accumulate, the complete enzyme fails to form efficiently, and cellular respiration is compromised. This assembly defect reduces the cell's capacity to generate ATP through oxidative phosphorylation, forcing greater reliance on less efficient metabolic pathways.
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Chromosome location
NDUFAF6 is located on the long arm of chromosome 8 at position 22.1, designated as 8q22.1. The gene spans this chromosomal region and encodes a protein of 333 amino acids that is imported into mitochondria to carry out its assembly function.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in NDUFAF6 typically result in loss of protein function, preventing the gene from producing a working assembly factor. These variants may include missense changes that disrupt protein folding or stability, nonsense variants that create premature stop codons, and small insertions or deletions that shift the reading frame. The consequence is impaired complex I assembly and mitochondrial dysfunction.
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.337C>T | p.Arg113Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 17 |
c.420+784C>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 17 |
c.485del | p.Asn162fs | Pathogenic/Likely pathogenic | ★★☆☆ | NDUFAF6-related disorder |
c.559_563del | p.Tyr187fs | Pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 17 |
c.561C>G | p.Tyr187Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
g.(?_96057753)_(96064478_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.440_441insTT | p.Leu147_Thr148insTer | Pathogenic | ★☆☆☆ | not provided |
c.478-972_580+533del | - | Pathogenic | ★☆☆☆ | Mitochondrial complex I deficiency, nuclear type 17 |
c.485_492dup | p.Asp165fs | Pathogenic | ★☆☆☆ | not provided |
c.485dup | p.Asn162fs | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
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
Pathogenic variants in NDUFAF6 cause mitochondrial disorders characterised by complex I deficiency. Clinical features often include neurological manifestations such as movement disorders, dystonia, and basal ganglia abnormalities visible on brain imaging. Some individuals present with childhood-onset symptoms affecting motor control and cognitive development, whilst metabolic disturbances may also occur. The severity and specific features vary between affected individuals, reflecting the broad impact of mitochondrial dysfunction on multiple organ systems.
No disease links recorded for this gene in our reference set.
UK clinical status
NDUFAF6 is included on several NHS Genomic Medicine Service gene panels related to mitochondrial and metabolic disorders. The gene appears on the Mitochondrial disorders panel and the Mitochondrial disorder with complex I deficiency panel, both with green classification indicating strong evidence for clinical use. NDUFAF6 is also listed on panels for Childhood onset dystonia, chorea or related movement disorder, Structural basal ganglia disorders, Likely inborn error of metabolism, Possible mitochondrial disorder - nuclear genes, and Undiagnosed metabolic disorders. This broad panel membership reflects the varied clinical presentations associated with complex I assembly defects.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does NDUFAF6 do in the cell?
NDUFAF6 produces a protein that helps assemble complex I, the first and largest enzyme in the mitochondrial respiratory chain. This assembly factor ensures that the many subunits of complex I are correctly positioned and stabilised during enzyme construction, enabling efficient cellular energy production.
What happens when NDUFAF6 is not working properly?
When NDUFAF6 is non-functional, complex I cannot assemble correctly, leading to reduced enzyme activity and impaired mitochondrial energy production. This deficiency particularly affects high-energy tissues such as the brain, resulting in neurological symptoms including movement disorders and developmental concerns.
How are NDUFAF6-related conditions inherited?
The inheritance pattern for NDUFAF6-related conditions can vary. Many mitochondrial complex assembly factor disorders follow autosomal recessive inheritance, meaning an individual typically requires pathogenic variants in both gene copies to develop disease, but the specific pattern depends on the nature of the variants involved.