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PEX14
peroxisomal biogenesis factor 14
PEX14 is located on the short (p) arm of chromosome 1, at band 1p36.22. Arm ratio per GRCh38 - banding schematic.
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Overview
PEX14 (peroxisomal biogenesis factor 14) is located on chromosome 1 and encodes a protein essential for peroxisome assembly. Peroxisomes are membrane-bound organelles present in nearly all cells, responsible for breaking down very long chain fatty acids, synthesising certain lipids, and detoxifying reactive oxygen species. The PEX14 protein functions as part of the machinery that imports newly made proteins into peroxisomes, ensuring these organelles can carry out their metabolic functions. When both copies of PEX14 carry pathogenic variants, peroxisome formation fails or is severely impaired, resulting in the accumulation of toxic metabolites that damage the brain, liver, kidneys and other tissues. These conditions follow an autosomal recessive inheritance pattern, meaning affected individuals inherit one altered copy from each parent.
What the gene does
The PEX14 protein serves as a docking component within the peroxisomal membrane, facilitating the import of proteins destined for the peroxisome interior. Newly synthesised proteins carrying specific signal sequences are recognised in the cytoplasm and delivered to the peroxisome surface, where PEX14 acts as an anchor point for the import machinery. This protein works in concert with other peroxins to form a transient pore through which cargo proteins enter the organelle. Without functional PEX14, cells cannot efficiently transport enzymes required for fatty acid oxidation and other peroxisomal reactions into the organelle, leading to empty or severely dysfunctional peroxisomes. The resulting metabolic disruption affects tissues with high energy demands or those requiring lipid processing, particularly the developing nervous system, liver and adrenal glands. The protein's role is highly conserved across species, reflecting the fundamental importance of peroxisome biogenesis for cellular health.
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Chromosome location
PEX14 is located on the short arm of chromosome 1 at position p36.22, a region near the chromosome's tip. The gene spans genomic DNA and encodes a protein of 377 amino acids. This chromosomal region contains numerous genes, and the p36 band has been associated with various genetic conditions when deletions or duplications occur. The compact size and organisation of PEX14 reflect its specialised cellular function.
Protein structure
The PEX14 protein comprises 377 amino acids with disordered regions at both termini. The N-terminal disordered region spans amino acids 1-24, whilst an extensive C-terminal disordered region extends from amino acids 230-377. These intrinsically disordered segments lack stable three-dimensional structure and instead remain flexible, a property that may facilitate the protein's role in forming dynamic import complexes at the peroxisomal membrane. The central portion of the protein is thought to mediate interactions with other peroxins and cargo-receptor complexes, though detailed structural characterisation of individual functional domains beyond these disordered regions has not been fully established experimentally.
Key variants
Pathogenic variants in PEX14 have been identified throughout the gene, including missense changes that alter single amino acids, nonsense variants that introduce premature stop signals, and small insertions or deletions that disrupt the reading frame. The severity of peroxisomal dysfunction generally correlates with how extensively the variants impair protein function. Complete loss of PEX14 activity typically results in more severe phenotypes presenting in infancy, whilst variants retaining partial function may present with milder features or later onset.
Sample of pathogenic variants
7 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 |
|---|---|---|---|---|
g.(?_10535024)_(10535079_?)del | - | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder, complementation group K |
g.(?_10535024)_(10596374_?)del | - | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder, complementation group K |
g.(?_10535024)_(10687440_?)del | - | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder, complementation group K |
g.(?_10596250)_(10596374_?)del | - | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder, complementation group K |
g.10599291_10599292insTAAAGCAGCAATAAACTCAAGGATAAATTAAGGAAATTGAATGAGCCACATTTGGAAGCAGTGTTGAGGCTAATATTCTGTCGCTTAAGGTTAAATTGCAACTGAGAGAGGTTCCGGAGAATCTGAAATCGGGGAGGCAACTTACTAGGATGCGAGGCATTCTGTGGCTGTAAAGGTCTTTGCTCAGTGAAGATTCTGTTGCAGCTATGGACACTGACAAAAGGTACTCACCTGCAATGATGTCCTCTTCTCCCCAGGGCTGACAGATGAAGAGATTGATATGGCCTTCCAGCAGTCGGGCACTGCTGCCG | - | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder, complementation group K |
c.109C>T | p.Gln37Ter | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder, complementation group K |
g.(25377_66267)_(66353_129292)del | - | Pathogenic | - | Peroxisome biogenesis disorder 13A (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
Biallelic pathogenic variants in PEX14 cause peroxisomal biogenesis disorders, a group of rare metabolic conditions characterised by impaired peroxisome assembly. Clinical features often include developmental delay, neurological deterioration, liver dysfunction, distinctive facial features, skeletal abnormalities and vision problems due to retinal degeneration. The spectrum ranges from severe neonatal presentations resembling Zellweger syndrome to milder childhood-onset forms. Biochemical hallmarks include elevated very long chain fatty acids, abnormal bile acid intermediates and plasmalogen deficiency. Early diagnosis through metabolic testing can guide supportive care, though treatment options remain limited and primarily focus on managing complications.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PEX14 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, PEX14 appears on multiple clinical panels with green classification, reflecting strong evidence for its role in disease. These include the Peroxisomal disorders panel, Likely inborn error of metabolism panel, Intellectual disability panel, and Neonatal cholestasis panel, amongst others. The gene's inclusion across panels for conditions ranging from foetal anomalies to adult onset leukodystrophy reflects the broad phenotypic spectrum associated with peroxisomal dysfunction. Green status indicates that variants in this gene are routinely analysed when the clinical presentation aligns with these panels, supporting timely diagnosis for affected families.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does PEX14 follow?
PEX14-related conditions follow an autosomal recessive pattern. This means an individual must inherit a pathogenic variant from both parents to develop the disorder. Carriers with one altered copy typically show no symptoms.
How are PEX14-related conditions diagnosed?
Diagnosis typically involves biochemical testing showing elevated very long chain fatty acids and other peroxisomal metabolites, followed by genetic testing to identify pathogenic variants in PEX14 or related genes. Early metabolic screening in infants with suggestive features can expedite diagnosis.
Are there treatments for peroxisomal disorders caused by PEX14 variants?
No cure currently exists for PEX14-related peroxisomal disorders. Management focuses on supportive care including nutritional support, treatment of liver dysfunction, seizure control, and monitoring for complications. Research into potential therapies including dietary interventions and enzyme replacement is ongoing.