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PEX3
peroxisomal biogenesis factor 3
PEX3 is located on the long (q) arm of chromosome 6, at band 6q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
PEX3 encodes a protein that plays a fundamental role in peroxisome biogenesis. Peroxisomes are small membrane-bound compartments found in nearly all cells, where they carry out essential metabolic reactions including the breakdown of very long-chain fatty acids and the synthesis of certain lipids. The PEX3 protein acts as an anchor in the peroxisome membrane and recruits other proteins necessary for building functional peroxisomes. Without properly functioning PEX3, cells cannot maintain healthy peroxisomes, leading to the accumulation of toxic metabolic products. Pathogenic variants in PEX3 follow an autosomal recessive inheritance pattern, meaning an individual must inherit two altered copies to develop disease.
What the gene does
The PEX3 protein functions as a membrane anchor that initiates peroxisome formation. It embeds itself into the peroxisome membrane early in the organelle's assembly process and serves as a docking site for other peroxisomal proteins. Specifically, PEX3 recruits PEX19, a protein that escorts newly synthesised peroxisomal membrane proteins to their destination. This interaction between PEX3 and PEX19 is critical for populating the peroxisome membrane with the full complement of proteins required for metabolic function. Once established, peroxisomes carry out diverse biochemical processes including beta-oxidation of very long-chain fatty acids, alpha-oxidation of branched-chain fatty acids, and synthesis of plasmalogens, which are specialised lipids important for myelin formation in the nervous system. The PEX3 protein therefore serves as a foundation upon which functional peroxisomes are built.
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Chromosome location
PEX3 is located on the long arm of chromosome 6 at position 6q24.2. This chromosomal region contains multiple genes, and the specific genomic context may influence expression or regulation of PEX3 in different tissues. The encoded protein is 373 amino acids in length.
Protein structure
The PEX3 protein contains distinct functional regions that enable its role in peroxisome assembly. The N-terminal region, spanning amino acids 1 to 45, is responsible for targeting the protein to peroxisomes, ensuring it localises correctly within the cell. A second critical region, encompassing amino acids 120 to 136, mediates the protein's interaction with PEX19, the chaperone that delivers membrane proteins to developing peroxisomes. These structural elements work together to position PEX3 at the peroxisome membrane and enable it to recruit the molecular machinery needed for organelle biogenesis.
Key variants
Pathogenic variants in PEX3 typically result in loss of protein function, preventing normal peroxisome formation. Most disease-causing variants are found in individuals with severe peroxisomal biogenesis disorders. Because PEX3-related conditions follow autosomal recessive inheritance, carriers of a single pathogenic variant generally remain unaffected. Genetic testing can identify variants through sequencing analysis, and variant interpretation considers the location within functional domains, the type of genetic change, and its predicted impact on protein activity.
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.17G>A | p.Trp6Ter | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.288-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | PEX3-related disorder |
c.292_302del | p.Ser98fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 10A (Zellweger) |
c.766C>T | p.Arg256Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PEX3-related disorder |
c.856C>T | p.Arg286Ter | Pathogenic | ★★☆☆ | not provided |
c.227_228del | p.Leu76fs | Pathogenic | ★☆☆☆ | not provided |
c.284dup | p.Asn95fs | Pathogenic | ★☆☆☆ | not provided |
c.494T>G | p.Leu165Ter | Pathogenic | ★☆☆☆ | not provided |
c.699_700dup | p.Leu234fs | Pathogenic | ★☆☆☆ | not provided |
c.863_864insAT | p.Phe288fs | Pathogenic | ★☆☆☆ | not provided |
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 PEX3 cause peroxisomal biogenesis disorders, a group of severe metabolic conditions that typically present in infancy or early childhood. These disorders result from the failure to form functional peroxisomes, leading to impaired fatty acid metabolism and accumulation of toxic substrates. Clinical features often include developmental delay, seizures, liver dysfunction, distinctive facial features, and progressive neurological decline. The severity of disease generally correlates with the degree of residual PEX3 function, though most affected individuals experience profound multisystem involvement.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PEX3 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
PEX3 appears on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical relevance across several diagnostic pathways. The gene holds green (high evidence) classification on panels including Peroxisomal disorders, Likely inborn error of metabolism, Inherited white matter disorders, Intellectual disability, Neonatal cholestasis, and Fetal anomalies. Additional panel memberships include Adult onset leukodystrophy, Arthrogryposis, Bilateral congenital or childhood onset cataracts, Fetal hydrops, Malformations of cortical development, Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification. These panel inclusions support the use of PEX3 testing in NHS diagnostic services when clinical features suggest a peroxisomal disorder.
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 PEX3 variant?
Carriers have one pathogenic variant and one working copy of PEX3, which is typically sufficient for normal peroxisome formation. Carriers do not develop peroxisomal disorders themselves but can pass the variant to their children.
How are PEX3-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 PEX3. Some cases are identified through newborn screening programmes or when clinical features raise suspicion of a peroxisomal disorder.
Why is PEX3 included on carrier screening panels?
PEX3 is included because pathogenic variants cause severe autosomal recessive disorders, and carrier screening allows prospective parents to understand their reproductive risks. Couples who are both carriers have a 25% chance with each pregnancy of having an affected child.