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PEX2
peroxisomal biogenesis factor 2
PEX2 is located on the long (q) arm of chromosome 8, at band 8q21.13. Arm ratio per GRCh38 - banding schematic.
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Overview
PEX2 is located on chromosome 8 and encodes peroxisomal biogenesis factor 2, a component of the peroxisomal protein import machinery. Peroxisomes are small membrane-bound organelles present in nearly all human cells, responsible for breaking down very long-chain fatty acids and neutralising reactive oxygen species. The PEX2 protein works as part of a multi-subunit complex that recognises and transports newly synthesised enzymes across the peroxisomal membrane.
When PEX2 function is lost or severely impaired, peroxisomes fail to assemble properly, leading to accumulation of toxic metabolites and disruption of normal cellular processes. This results in a spectrum of inherited conditions collectively known as peroxisomal biogenesis disorders, which typically present in infancy with developmental delay, liver dysfunction, and distinctive facial features. PEX2-related conditions follow an autosomal recessive inheritance pattern, meaning two pathogenic variants - one inherited from each parent - are required for disease manifestation.
What the gene does
The PEX2 protein is a core component of the peroxisomal importomer, a molecular machine that transports proteins into peroxisomes. Peroxisomes contain more than 50 different enzymes involved in lipid metabolism, including the breakdown of very long-chain fatty acids through beta-oxidation, and the synthesis of plasmalogens - phospholipids essential for myelin formation in the nervous system.
PEX2 functions alongside other peroxin proteins to form a docking and translocation channel in the peroxisomal membrane. The protein recognises cargo destined for the peroxisome interior by interacting with receptor proteins that bind peroxisomal targeting signals. After cargo delivery, PEX2 participates in recycling these receptors back to the cytoplasm for another round of import. Without functional PEX2, newly synthesised peroxisomal enzymes remain stranded in the cytoplasm, unable to reach their proper location. This leads to empty peroxisome membrane structures that lack the enzymatic machinery required to carry out normal metabolic functions, resulting in accumulation of very long-chain fatty acids and impaired plasmalogen synthesis.
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Chromosome location
PEX2 is located on the long arm of chromosome 8 at position 21.13 (8q21.13). The gene spans approximately 17 kilobases of genomic DNA and comprises 5 exons. The coding sequence produces a transcript of approximately 1.2 kilobases, which is translated into a 305-amino acid protein. The genomic region surrounding PEX2 is relatively gene-dense, though no structural variations affecting neighbouring genes have been specifically associated with PEX2-related phenotypes.
Protein structure
The PEX2 protein is 305 amino acids in length and contains a RING-type zinc finger domain spanning amino acids 244-284. This RING domain is critical for the protein's function in peroxisomal biogenesis, likely mediating protein-protein interactions with other components of the import machinery. The PEX2 protein is anchored in the peroxisomal membrane through two predicted transmembrane segments, with the majority of the protein, including the RING domain, facing the cytoplasm. The zinc finger motif coordinates zinc ions through conserved cysteine and histidine residues, creating a stable structural scaffold that enables PEX2 to interact with receptor proteins during the import cycle.
Key variants
Pathogenic variants throughout PEX2 have been identified in individuals with peroxisomal biogenesis disorders. Both missense variants affecting critical residues within the RING domain and truncating variants that produce shortened, non-functional proteins have been reported. The severity of the resulting condition typically correlates with the degree of residual protein function, with null variants generally associated with the most severe presentations. Carrier frequency varies across populations, with certain pathogenic variants identified as founder mutations in specific ethnic groups.
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.118del | p.Cys40fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5A (Zellweger) |
c.157G>T | p.Glu53Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5A (Zellweger) |
c.171del | p.Ala58fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5B |
c.183G>A | p.Trp61Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5A (Zellweger) |
c.24_25del | p.Lys9fs | Pathogenic/Likely pathogenic | ★★☆☆ | PEX2-related disorder |
c.272dup | p.Pro91_Asn92insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5A (Zellweger) |
c.310del | p.Ile104fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5A (Zellweger) |
c.314G>A | p.Trp105Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Zellweger spectrum disorders |
c.325dup | p.Cys109fs | Pathogenic/Likely pathogenic | ★★☆☆ | Zellweger spectrum disorders |
c.502G>T | p.Glu168Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 5A (Zellweger) |
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 PEX2 cause conditions within the Zellweger spectrum, a continuum of peroxisomal biogenesis disorders. The most severe form, Zellweger syndrome, presents in the neonatal period with profound hypotonia, seizures, liver dysfunction, and distinctive craniofacial features. Affected infants often have hearing and vision impairment, and typically survive only the first year of life. Intermediate forms include neonatal adrenoleukodystrophy, whilst the mildest presentation, infantile Refsum disease, may allow survival into childhood or adolescence with developmental delay and progressive neurological decline. All forms share biochemical hallmarks including elevated very long-chain fatty acids in plasma and reduced plasmalogen levels in red blood cells.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PEX2 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
PEX2 appears on multiple NHS Genomic Medicine Service gene panels with green classification, indicating strong evidence for clinical validity. The gene is included in panels for peroxisomal disorders, likely inborn errors of metabolism, and undiagnosed metabolic disorders, reflecting its role in a recognisable group of inherited conditions. PEX2 is also listed on panels for specific clinical presentations seen in peroxisomal biogenesis disorders, including intellectual disability (R29), inherited white matter disorders, neonatal cholestasis, retinal disorders (R32), bilateral congenital or childhood onset cataracts (R31), and foetal anomalies (R21). Additional panel memberships include adult onset leukodystrophy (R62), arthrogryposis (R83), foetal hydrops, malformations of cortical development, white matter disorders and cerebral calcification, and the Developmental Disorders Genotype-to-Phenotype database (DDG2P). This extensive panel representation reflects the multi-system nature of peroxisomal dysfunction and ensures PEX2 sequencing is offered when clinically appropriate across diverse presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a PEX2 variant?
A carrier has one pathogenic variant in PEX2 and one normal working copy. Carriers do not develop peroxisomal disorders themselves, as the single functional gene copy provides sufficient protein for normal peroxisome function. However, if both parents are carriers, each of their children has a 25% chance of inheriting two pathogenic variants and being affected.
How are PEX2-related conditions diagnosed?
Diagnosis typically begins with biochemical testing showing elevated very long-chain fatty acids and reduced plasmalogens in blood. Genetic testing confirming pathogenic variants in PEX2 establishes the specific molecular cause. In some cases, liver biopsy or skin fibroblast studies may be performed to assess peroxisome structure and function.
Is PEX2 testing available through the NHS?
Yes, PEX2 sequencing is available through the NHS Genomic Medicine Service for individuals meeting clinical criteria on relevant gene panels, including those with suspected peroxisomal disorders or unexplained metabolic presentations. Referral is made through clinical genetics services when a peroxisomal biogenesis disorder is suspected based on clinical and biochemical findings.