PEX26 — Peroxisome biogenesis factor 26
The PEX26 gene provides instructions for making a protein that is essential for the formation and normal function of peroxisomes. Peroxisomes are small compartments within cells that act like recycling centers; they break down toxic substances and certain fats, and help build important molecules needed for the brain and lungs to work properly. The PEX26 protein acts as an anchor on the surface of peroxisomes, helping to pull in the enzymes needed for these processes. When there are harmful changes (mutations) in the PEX26 gene, peroxisomes cannot form correctly or function properly. This leads to a buildup of toxic substances and a lack of essential molecules in the body. Depending on the severity of the mutation, this can cause a group of conditions known as Zellweger spectrum disorders. In severe cases, babies are born with serious brain, liver, and vision problems, and often do not survive past their first year. In milder cases, children may develop vision loss, hearing loss, and developmental delays later in childhood. Currently, treatments for PEX26-related conditions are mainly supportive, focusing on managing symptoms like seizures and feeding difficulties. However, researchers are exploring new therapies, including special diets, medications to improve peroxisome function, and potential gene therapies to help restore normal cellular processes and improve the quality of life for affected individuals.
Gene description: PEX26 encodes the peroxisome biogenesis factor 26, a membrane protein essential for peroxisome assembly and function. Mutations in this gene lead to peroxisome biogenesis disorders, including Zellweger syndrome spectrum disorders, which cause severe neurological, hepatic, and visual impairments.
Patient and family guide: The PEX26 gene provides instructions for making a protein that is essential for the formation and normal function of peroxisomes. Peroxisomes are small compartments within cells that act like recycling centers; they break down toxic substances and certain fats, and help build important molecules needed for the brain and lungs to work properly. The PEX26 protein acts as an anchor on the surface of peroxisomes, helping to pull in the enzymes needed for these processes. When there are harmful changes (mutations) in the PEX26 gene, peroxisomes cannot form correctly or function properly. This leads to a buildup of toxic substances and a lack of essential molecules in the body. Depending on the severity of the mutation, this can cause a group of conditions known as Zellweger spectrum disorders. In severe cases, babies are born with serious brain, liver, and vision problems, and often do not survive past their first year. In milder cases, children may develop vision loss, hearing loss, and developmental delays later in childhood. Currently, treatments for PEX26-related conditions are mainly supportive, focusing on managing symptoms like seizures and feeding difficulties. However, researchers are exploring new therapies, including special diets, medications to improve peroxisome function, and potential gene therapies to help restore normal cellular processes and improve the quality of life for affected individuals.
Gene function: PEX26 functions as a peroxisomal membrane anchor that recruits the PEX1-PEX6 AAA-ATPase complex to peroxisomes. This complex is crucial for the recycling of the peroxisomal targeting signal 1 (PTS1) receptor, PEX5, which mediates the import of matrix proteins into peroxisomes.
Protein structure: PEX26 is a 305-amino acid single-pass type II membrane protein. It contains a transmembrane segment and an N-terminal region that interacts with the PEX1-PEX6 complex and PEX14, anchoring them to the peroxisomal membrane.
Molecular function: PEX26 is an integral peroxisomal membrane protein that acts as a docking factor for the PEX1-PEX6 AAA-ATPase complex. By anchoring this complex to the peroxisome membrane, PEX26 facilitates the extraction and recycling of the PEX5 receptor from the peroxisomal membrane back to the cytosol after it has delivered matrix proteins. This process is essential for continuous peroxisomal matrix protein import, which is required for lipid metabolism, including the beta-oxidation of very long-chain fatty acids and the biosynthesis of ether phospholipids like plasmalogens.
Mutation spectrum: The mutation spectrum of PEX26 includes missense, nonsense, frameshift, and splicing mutations. Missense mutations are the most common and are often associated with milder phenotypes like NALD and IRD due to residual protein function. Nonsense, frameshift, and splicing mutations typically result in a truncated, non-functional protein, leading to the severe Zellweger syndrome phenotype. A common missense variant is c.292C>T, while c.153C>A (p.F51L) has been linked to nonsyndromic hearing loss.
Clinical significance: Pathogenic mutations in PEX26 cause peroxisome biogenesis disorders (PBDs) in the Zellweger syndrome spectrum (ZSS). These mutations disrupt the PEX1-PEX6 AAA-ATPase complex formation, impairing peroxisomal matrix protein import and leading to peroxisome dysfunction. This results in the accumulation of very long-chain fatty acids (VLCFAs) and a deficiency of plasmalogens. Severe null mutations typically cause Zellweger syndrome, characterized by profound neurological dysfunction, craniofacial dysmorphism, and early death. Milder missense mutations often result in neonatal adrenoleukodystrophy (NALD) or infantile Refsum disease (IRD), which present with progressive visual decline, sensorineural hearing loss, leukodystrophy, and variable developmental delays.
Inheritance: Autosomal Recessive
Chromosomal location: 22q11.21
Research and therapeutic approaches: Current management for PEX26-related disorders is primarily supportive and multidisciplinary, addressing specific symptoms like seizures, feeding issues, and vision/hearing loss. Cholic acid therapy is used to treat liver disease by reducing toxic bile acid intermediates. Experimental therapies under research include small molecule compounds like betaine to improve peroxisomal assembly, docosahexaenoic acid (DHA) supplementation, and drugs targeting pexophagy (e.g., hydroxychloroquine). Gene therapy approaches are also being investigated in animal models to potentially rescue peroxisome function and treat vision loss in milder phenotypes.