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PEX6
peroxisomal biogenesis factor 6
PEX6 is located on the short (p) arm of chromosome 6, at band 6p21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
PEX6 encodes peroxisomal biogenesis factor 6, a component of the cellular machinery that enables peroxisomes to import the enzymes they require for normal function. Peroxisomes are membrane-bound organelles present in nearly all human cells, responsible for breaking down very long-chain fatty acids, synthesising certain lipids, and neutralising toxic reactive oxygen species. The PEX6 protein works alongside other peroxins to transport newly made enzymes across the peroxisomal membrane. Disruption of this import system prevents peroxisomes from performing their metabolic roles, with particularly severe consequences during foetal development and early childhood. Biallelic pathogenic variants in PEX6 account for a substantial proportion of cases within the Zellweger spectrum, a group of autosomal recessive conditions characterised by impaired peroxisome assembly.
What the gene does
The PEX6 protein functions as an AAA-ATPase (ATPase associated with diverse cellular activities), using energy from ATP hydrolysis to drive the import of peroxisomal matrix proteins. Peroxisomal enzymes are synthesised in the cytoplasm with specific targeting signals, then recognised by receptor proteins that ferry them to the peroxisome surface. PEX6 forms a complex with another peroxin, PEX1, and together they extract the receptor proteins from the peroxisomal membrane after cargo delivery, recycling the receptors for further rounds of import. This ATP-dependent extraction step is essential for maintaining a functional import cycle. Without adequate PEX6 activity, receptor proteins become trapped in the membrane, cargo import stalls, and peroxisomes remain deficient in the enzymes needed for fatty acid breakdown and other metabolic processes. The resulting accumulation of very long-chain fatty acids and other substrates contributes to the multisystem pathology observed in affected individuals.
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Chromosome location
PEX6 is located on the short arm of chromosome 6 at band 6p21.1. The gene spans approximately 43 kilobases of genomic DNA and comprises 17 exons. This chromosomal region is gene-rich and includes other loci involved in immune function and metabolism, though PEX6 variants specifically affect peroxisome biogenesis rather than immune responses.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The 980-amino-acid PEX6 protein contains two AAA-ATPase modules that bind and hydrolyse ATP, generating the mechanical force required to extract receptor proteins from the peroxisomal membrane. These ATPase regions share structural features with other AAA-family proteins involved in protein unfolding and membrane remodelling, though the specific three-dimensional arrangement and regulatory elements within PEX6 remain areas of ongoing research.
Key variants
Pathogenic variants in PEX6 are distributed across the gene, with both missense changes and truncating variants reported. Some variants abolish protein production entirely, whilst others produce a protein with reduced ATPase activity or impaired ability to interact with PEX1. The severity of clinical manifestations often correlates with the degree of residual peroxisomal function, though genotype-phenotype relationships are not absolute. Certain variants are more common in specific populations due to founder effects.
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.1036C>T | p.Gln346Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Heimler syndrome 2 |
c.1229_1232delinsGA | p.Tyr410_Met411delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Heimler syndrome 2 |
c.1262G>A | p.Trp421Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 4A (Zellweger) |
c.1263G>A | p.Trp421Ter | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.1287_1288del | p.Trp430fs | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.1409_1410delinsA | p.Gly470fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.1415dup | p.Gly473fs | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.1A>T | p.Met1Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Heimler syndrome 2 |
c.2359del | p.Glu787fs | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.2807-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Heimler syndrome 2 |
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
Biallelic pathogenic variants in PEX6 cause Zellweger spectrum disorder, an autosomal recessive condition encompassing a range of severity from neonatal-lethal Zellweger syndrome to milder forms with later onset and longer survival. Affected individuals typically present with hypotonia, seizures, distinctive facial features, liver dysfunction, and impaired vision and hearing. Neurological development is significantly affected, and many cases involve skeletal abnormalities and renal cysts. The spectrum reflects variable residual peroxisomal function, with milder presentations sometimes associated with variants that retain partial protein activity.
- Zellweger spectrum disorder Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic PEX6 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
PEX6 is designated a green gene (high evidence for disease association) on multiple NHS Genomic Medicine Service panels, reflecting its well-established role in peroxisomal disorders. It appears on panels including Peroxisomal Disorders, Likely Inborn Error of Metabolism, Intellectual Disability, Neonatal Cholestasis, Cholestasis, Fetal Anomalies, Retinal Disorders, Inherited White Matter Disorders, and Ataxia and Cerebellar Anomalies. This broad panel representation underscores the multisystem nature of PEX6-related disease, which can present with hepatic, neurological, ophthalmological, or metabolic features. Inclusion on these panels means that PEX6 sequencing is part of standard diagnostic pathways for patients with compatible clinical presentations within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between Zellweger syndrome and other conditions on the Zellweger spectrum?
Zellweger spectrum disorder represents a continuum of severity. Zellweger syndrome is the most severe form, typically presenting in the newborn period with profound neurological impairment and often proving fatal in infancy. Milder presentations may feature later onset, slower progression, and longer survival, though all share the underlying defect in peroxisome assembly.
How is PEX6-related Zellweger spectrum disorder inherited?
This condition follows autosomal recessive inheritance, meaning an affected individual has inherited a pathogenic variant in both copies of PEX6, one from each parent. Parents who each carry one variant typically have no symptoms themselves but have a 25% chance with each pregnancy of having an affected child.
Can carrier screening detect PEX6 variants?
Yes, carrier screening can identify individuals who carry one pathogenic PEX6 variant. If both partners in a couple are found to be carriers, they may wish to discuss reproductive options and the availability of prenatal or preimplantation genetic testing with a healthcare provider or genetic counsellor.