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PEX26
peroxisomal biogenesis factor 26
PEX26 is located on the long (q) arm of chromosome 22, at band 22q11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
PEX26 encodes peroxisomal biogenesis factor 26, a membrane protein integral to the formation and maintenance of peroxisomes. These small organelles conduct numerous metabolic reactions, including the breakdown of very-long-chain fatty acids and the synthesis of plasmalogens, specialised lipids abundant in myelin and cell membranes. When PEX26 function is compromised through pathogenic variants, peroxisomes fail to assemble properly, leading to toxic accumulation of metabolites and deficiency of essential lipids. The resulting peroxisomal biogenesis disorders manifest with severe neurological impairment, liver dysfunction, and skeletal abnormalities. PEX26-related conditions follow an autosomal recessive inheritance pattern, meaning affected individuals inherit two non-functioning copies of the gene.
What the gene does
The PEX26 protein functions as a docking component within the peroxisomal membrane, facilitating the import of other proteins required for organelle assembly. Peroxisomes rely on a complex machinery of peroxin proteins to bring newly synthesised enzymes from the cytoplasm into the organelle interior. PEX26 anchors this import machinery to the membrane, enabling the translocation of proteins tagged with specific targeting signals. Without functional PEX26, the peroxisome membrane forms but remains unable to import the matrix proteins necessary for metabolic activity. This results in empty membrane structures known as peroxisome ghosts, which lack the enzymatic capacity to perform beta-oxidation of fatty acids, plasmalogen synthesis, or hydrogen peroxide detoxification. The metabolic consequences extend across multiple organ systems, particularly affecting tissues with high energy demands such as the brain and liver.
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Chromosome location
PEX26 is located on the long arm of chromosome 22 at position 11.21, designated as 22q11.21. This chromosomal region contains numerous genes, and while the band itself has been associated with deletion syndromes affecting multiple genes, PEX26-related disorders arise from specific variants within the gene rather than large chromosomal rearrangements. The gene spans a relatively compact genomic segment encoding the 305-amino-acid protein.
Protein structure
The PEX26 protein comprises 305 amino acids with a disordered region spanning amino acids 1 to 20 at the N-terminus. This disordered segment likely provides flexibility for protein-protein interactions with other components of the peroxisomal import machinery. The protein contains transmembrane segments that anchor it within the peroxisomal membrane, positioning functional domains appropriately for recruitment of cytosolic peroxin complexes. The membrane topology ensures that specific regions face the cytoplasm, where they can interact with proteins destined for import, whilst other portions remain embedded within or facing the organelle lumen.
Key variants
Pathogenic variants in PEX26 disrupt the protein's ability to anchor and coordinate the peroxisomal import machinery. Loss-of-function variants include nonsense changes that introduce premature stop codons, frameshift variants resulting from small insertions or deletions, and missense variants affecting critical amino acids required for membrane insertion or protein interactions. The severity of peroxisomal biogenesis disorders can vary depending on residual protein function, with complete loss of activity typically causing more severe phenotypes presenting in the neonatal period.
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.185G>A | p.Trp62Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.190_191del | p.Leu65fs | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.230+1G>T | - | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.329_330del | p.Tyr110fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.34del | p.Leu12fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7B |
c.354del | p.Val120fs | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.37_38del | p.Arg13fs | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.436C>T | p.Gln146Ter | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.574C>T | p.Arg192Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (Zellweger) |
c.613del | p.Gln205fs | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 7A (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 PEX26 cause peroxisomal biogenesis disorders, a spectrum of conditions affecting multiple organ systems. The most severe presentation, Zellweger spectrum disorder, encompasses conditions previously classified separately as Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Affected individuals typically present with profound neurological impairment, characteristic facial features, liver disease, and skeletal abnormalities. Biochemical hallmarks include elevated very-long-chain fatty acids in blood, reduced plasmalogens, and accumulation of bile acid intermediates. The clinical severity correlates with the degree of peroxisomal dysfunction, though even milder presentations involve significant developmental challenges.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PEX26 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
PEX26 appears on multiple NHS Genomic Medicine Service gene panels reflecting the multi-system nature of peroxisomal biogenesis disorders. The gene holds green classification status on the Peroxisomal disorders panel and the Likely inborn error of metabolism panel (R98), indicating strong evidence for its role in these conditions. It also features on panels for Neonatal cholestasis, Cholestasis (R171), and Inherited white matter disorders, reflecting the hepatic and neurological manifestations of PEX26-related disease. Additional panel memberships include Intellectual disability (R29), Fetal anomalies (R21), and Adult onset leukodystrophy (R62), illustrating the variable age of onset and diverse clinical presentations associated with peroxisomal dysfunction.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for PEX26-related conditions?
PEX26-related peroxisomal biogenesis disorders follow an autosomal recessive inheritance pattern. An affected individual inherits one non-functioning copy of the gene from each parent, who are typically unaffected carriers.
How do PEX26 variants affect peroxisome function?
Pathogenic variants in PEX26 disrupt the protein's role in anchoring the peroxisomal import machinery, preventing essential enzymes from entering the organelle. This results in peroxisomes that cannot perform critical metabolic functions such as breaking down very-long-chain fatty acids or synthesising plasmalogens.
Can PEX26-related disorders be detected through carrier screening?
Yes, carrier screening can identify individuals who carry one pathogenic variant in PEX26. Couples who are both carriers have a 25% chance with each pregnancy of having an affected child, and genetic counselling can discuss reproductive options and testing strategies.