PEX1 gene

The PEX1 gene (Peroxisomal Biogenesis Factor 1) is a protein-coding gene located on chromosome 7q21.2. Alternatively spliced transcript variants have been found for this gene. An important paralog of this gene is PEX6.

The PEX1 gene encodes a member of the AAA ATPase family, a large group of ATPases associated with various cellular activities. The PEX1 protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and in peroxisome biogenesis.

Mutations in this gene are associated with peroxisomal diseases. These are hereditary disorders of peroxisome formation, the entire transport of proteins through the peroxisome membrane or even individual peroxisomal enzymes. The following diseases belong to this group:

• Neonatal adrenoleukodystrophy (muscle hypotonia, severe psychomotor retardation and failure to thrive. These infants are generally blind and deaf, and seizures occur in the first few weeks. A retinopathic "leopard spot" is common).
• Infantile Refsum disease (an enzyme deficiency interferes with the breakdown of phytanic acid in the peroxisomes. As a result, phytanic acid and related compounds accumulate in the tissues of the body. The accumulation of phytanic acid is toxic to the cells)
• Zellweger syndrome (bile acid synthesis disorder due to damage to the peroxisomes).
• Heimler syndrome 1 (sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to biallelic pathogenic PEX1 or PEX6 variations. The syndrome is one of the less severe forms of peroxisome biogenesis disorders).

Related metabolic pathways include peroxisomal lipid metabolism and ether lipid biosynthesis.

The protein is a component of the PEX1-PEX6 AAA ATPase complex, a protein-dislocase complex that mediates ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (Tamura S et al. 2001; Tamura S et al. 2001). The complex recognizes PEX5 monoubiquitinated at Cys-11 and pulls it out of the peroxisomal lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (Pedrosa AG et al. (2018).

1. Pedrosa AG et al. (2018) Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol. J Biol Chem 293: 11553-11563.
2. Tamura S et al. (2001) Phenotype-genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p-Pex6p interaction. Biochem J 357(Pt 2):417-426.