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PEX5
peroxisomal biogenesis factor 5
PEX5 is located on the short (p) arm of chromosome 12, at band 12p13.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The PEX5 gene encodes peroxisomal biogenesis factor 5, a cytosolic receptor protein responsible for recognising and importing soluble enzymes into peroxisomes. Peroxisomes are membrane-bound organelles that perform essential metabolic reactions, including the breakdown of very long-chain fatty acids, the synthesis of plasmalogens (specialised lipids critical for myelin formation), and the detoxification of reactive oxygen species. Because peroxisomes cannot synthesise their own proteins, they rely entirely on import machinery to acquire the enzymes needed for these processes.
PEX5 functions as the primary cargo receptor for peroxisomal matrix proteins bearing a type 1 peroxisomal targeting signal (PTS1), a short amino acid sequence typically found at the C-terminus of peroxisomal enzymes. Pathogenic variants in PEX5 disrupt this import mechanism, resulting in peroxisomal dysfunction and a spectrum of severe inherited metabolic disorders. The gene is inherited in an autosomal recessive pattern, meaning affected individuals carry biallelic pathogenic variants.
What the gene does
The PEX5 protein acts as a mobile receptor that shuttles between the cytosol and the peroxisomal membrane. It recognises cargo proteins containing the PTS1 signal, typically a tripeptide sequence such as serine-lysine-leucine at the C-terminus, through its C-terminal tetratricopeptide repeat (TPR) domain. After binding cargo in the cytosol, PEX5 docks at the peroxisomal membrane via interaction with the membrane-embedded docking complex, then releases its cargo into the peroxisomal matrix.
Following cargo release, PEX5 is either recycled back to the cytosol for further rounds of import or ubiquitinated and exported for degradation, a process that prevents receptor accumulation at the membrane. The N-terminal region of PEX5 contains amphipathic helices that facilitate membrane interactions and receptor recycling. Functional PEX5 is essential for maintaining appropriate levels of peroxisomal enzymes involved in lipid metabolism, including those required for beta-oxidation of very long-chain fatty acids and plasmalogen biosynthesis. Loss of PEX5 function leads to cytosolic accumulation of peroxisomal enzymes, preventing these critical metabolic reactions from occurring and resulting in toxic accumulation of substrates such as very long-chain fatty acids.
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Chromosome location
The PEX5 gene is located on the short arm of chromosome 12 at position 12p13.31. This chromosomal region contains multiple genes involved in diverse cellular functions. The genomic structure of PEX5 spans a region sufficient to encode a 639-amino-acid protein, though specific exon counts and intron-exon boundaries are catalogued in reference genome databases.
Protein structure
The PEX5 protein comprises 639 amino acids organised into functionally distinct regions. The N-terminal portion contains four amphipathic helices: amphipathic helix 1 (AH1) spanning amino acids 11-33, amphipathic helix 2 (AH2) from amino acids 81-99, amphipathic helix 3 (AH3) from amino acids 190-206, and amphipathic helix 4 (AH4) from amino acids 284-300. These helical regions facilitate membrane association and contribute to receptor recycling. A disordered region is present between amino acids 33 and 53, providing structural flexibility.
The central region contains multiple WxxxF/Y motifs (amino acids 118-122, 140-144, 159-163, 184-188, 243-247, 257-261, and 308-312) that mediate interactions with docking proteins at the peroxisomal membrane. An LVxEF motif at amino acids 62-66 also participates in protein-protein interactions during the import cycle. The C-terminal region houses two tetratricopeptide repeat (TPR) domains: TPR 1 spanning amino acids 335-368 and TPR 2 from amino acids 369-402. These TPR domains form a binding groove that specifically recognises the PTS1 signal on cargo proteins, enabling precise substrate selection for peroxisomal import.
Key variants
Pathogenic variants in PEX5 disrupt peroxisomal enzyme import through various mechanisms, including impaired cargo recognition, defective membrane docking, or failed receptor recycling. Variants may be missense changes affecting critical residues in the TPR domain that reduce PTS1 binding affinity, or truncating variants that eliminate essential functional domains. The severity of clinical manifestations often correlates with the degree of residual PEX5 function, with complete loss of activity associated with the most severe peroxisomal biogenesis disorders.
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.1255C>T | p.Gln419Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PEX5-related disorder |
c.1258C>T | p.Arg420Ter | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 2B |
c.1279C>T | p.Arg427Ter | Pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 5 |
c.1578T>A | p.Asn526Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.358C>T | p.Gln120Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 2B |
c.361G>T | p.Glu121Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 2B |
c.449-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 2B |
c.552-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 2B |
c.552G>A | p.Trp184Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PEX5-related disorder |
c.670G>T | p.Glu224Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 2B |
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 PEX5 cause peroxisomal biogenesis disorders within the Zellweger spectrum, a continuum of conditions characterised by impaired peroxisome function. The spectrum ranges from severe Zellweger syndrome, presenting in the neonatal period with profound neurological impairment, dysmorphic features, and hepatic dysfunction, to milder forms such as neonatal adrenoleukodystrophy and infantile Refsum disease. Common biochemical features include elevated very long-chain fatty acids, reduced plasmalogen levels, and accumulation of intermediates in bile acid synthesis. Clinical manifestations typically include developmental delay, hypotonia, seizures, vision and hearing impairment, and progressive neurodegeneration due to defective myelin formation.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PEX5 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
Within the NHS Genomic Medicine Service, PEX5 holds green (diagnostic-grade evidence) status across multiple clinical panels reflecting the diverse presentations of peroxisomal disorders. The gene appears on panels for peroxisomal disorders, inherited white matter disorders, likely inborn errors of metabolism, and intellectual disability. It is also included on panels addressing specific phenotypic features such as bilateral congenital or childhood onset cataracts, skeletal dysplasia, arthrogryposis, and foetal anomalies. This broad panel representation reflects the multi-system nature of peroxisomal biogenesis disorders and facilitates genetic diagnosis across various clinical specialties within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for PEX5-related conditions?
PEX5-related peroxisomal disorders follow an autosomal recessive inheritance pattern. An affected individual inherits one pathogenic variant from each parent, who are typically unaffected carriers. Each child of two carrier parents has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither variant.
How are peroxisomal biogenesis disorders diagnosed?
Diagnosis typically combines biochemical testing showing elevated very long-chain fatty acids and reduced plasmalogens in blood or fibroblasts with genetic testing confirming biallelic pathogenic variants in a peroxisomal biogenesis gene such as PEX5. Clinical features and imaging findings support the diagnosis, and genetic counselling is offered to families.
Why is PEX5 included on multiple NHS clinical panels?
Peroxisomal biogenesis disorders affect multiple organ systems simultaneously, causing diverse clinical presentations including neurological, hepatic, skeletal, and ophthalmological features. PEX5 appears on numerous panels to ensure genetic diagnosis is considered across the range of possible presenting symptoms, facilitating earlier identification and appropriate clinical management.