Disease relevance of PEX1

• PEX7 mutations cause the peroxisome biogenesis disorder (PBD) rhizomelic chondrodysplasia punctata (RCDP) [1].
• Comparison with gene microarray data revealed that 31% of the differentially regulated proteins correlate with altered mRNA expression in squamous cell lung carcinomas, including PEX1, MKK7 and HDAC3 for up-regulated proteins [2].
• This mutant (65TS) was produced by transforming a PEX2-defective mutant, Z65, with a mutant PEX2 gene, PEX2(E55K), derived from a patient with infantile Refsum disease, a milder form of peroxisome biogenesis disorder [3].
• RESULTS: Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness [4].
• Defects in the formation of the cerebral cortex and the cerebellum are a prominent feature of the peroxisome biogenesis disorder Zellweger syndrome and in mouse models for this disease [5].

High impact information on PEX1

• Thus, Pex26 recruits Pex6-Pex1 complexes to peroxisomes [6].
• Pex7p function is conserved between yeasts and humans, with defects in the human protein causing rhizomelic chondrodysplasia punctata (RCDP), a severe, lethal peroxisome biogenesis disorder characterized by aberrant targeting of several PTS2 peroxisomal proteins, but uncertainty remains about the subcellular localization of this receptor [7].
• In addition, we found that the PTS1 receptor was extremely unstable in the peroxin-deficient CG1, CG4, and CG8 cells [8].
• They proposed that PEX26 functions as the peroxisomal docking factor for the PEX1/PEX6 heterodimer [9].
• This model predicts that, once activated in an extraperoxisomal location, PEX1 moves to the peroxisome and completes the function of the PEX1/6 heterodimer [9].

Biological context of PEX1

• Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders [10].
• Molecular genetic and cell biology studies have shown that PEX1 is deficient in many CG1 patients [11].
• Temperature-sensitive mutation of PEX6 in peroxisome biogenesis disorders in complementation group C (CG-C): comparative study of PEX6 and PEX1 [12].
• The fifth mutation is a missense mutation (R798G) that attenuates, but does not abolish PEX1 function [13].
• In the present study, we used SSCP analysis to evaluate a series of patients belonging to CG1 for mutations in PEX1 and studied phenotype-genotype correlations [14].

Anatomical context of PEX1

• Collectively, these results demonstrate temperature-sensitive peroxisome assembly to be responsible for the mildness of the clinical features of PEX1 -defective IRD of CG1 [10].
• The mutant PEX1, termed HsPEX1G843D, gave rise to the same temperature-sensitive phenotype on CG1 CHO cell mutants upon transfection [10].
• These results suggested that Pex1p possesses two distinct oligomeric forms, a homo-oligomer in the cytosol and a hetero-oligomer on peroxisome membranes, possibly playing distinct functions in peroxisome biogenesis [15].
• Taking these results together, we consider it most likely that the stability of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibroblasts [16].
• In these studies, we have undertaken mutation analysis of PEX1 in skin fibroblast cell lines from Australasian Zellweger syndrome spectrum patients [17].

Associations of PEX1 with chemical compounds

• The role of peroxisomes, in which the glyoxylate pathway enzymes are localized in many organisms, was examined by mutation of two genes (PEX1 and PEX6) encoding AAA (ATPases associated with various cellular activities)-type proteins required for peroxisome formation [18].
• By mutational analysis, we demonstrate that a conserved arginine surrounded by hydrophobic residues is essential for lipid binding, despite very low sequence similarity between PEX1 and valosine-containing protein [19].
• The N-terminal domain of PEX1 appears to preferentially bind phosphatidylinositol 3-monophosphate and phosphatidylinositol 4-monophosphate, whereas the N-terminal domain of valosine-containing protein displays broad and nonspecific lipid binding [19].
• In bile of a patient with a peroxisome biogenesis disorder (Zellweger syndrome, ZS) LTE(4) was found to be slightly increased, whereas both omega-oxidation metabolites of LTE4, omega-hydroxy-LTE4 and omega-carboxy-LTE4, were highly increased (about 12-18 times) [20].
• Deletion of the hexokinase HXK2 gene reduced growth in the presence of glucose and suppressed the growth defect of the pex1 mutant on glucose [18].

Regulatory relationships of PEX1

• Stable overexpression of PEX11beta to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells [21].

Other interactions of PEX1

• In HEK293 cells, endogenous Pex1p was partly localized likely as a homo-oligomer in the cytoplasm, while Pex6p and Pex26p were predominantly localized on peroxisomes [15].
• Identification of a common PEX1 mutation in Zellweger syndrome [11].
• Previously we isolated human PEX16 encoding 336-amino acid-long peroxin Pex16p and showed that its dysfunction was responsible for Zellweger syndrome of complementation group D (group 9) [22].
• Alternatively, Pex19p might act as a multifunctional peroxin and participate in a number of these activities [23].
• Genomic structure of PEX13, a candidate peroxisome biogenesis disorder gene [24].

Analytical, diagnostic and therapeutic context of PEX1

• Immunoprecipitation of Pex1p using anti-Pex1p antibody resulted in concomitant recovery of 35S-Pex6p [25].
• Peroxisome biogenesis disorder should be included in the differential diagnosis of post-infantile onset of cerebral white matter disease[4]
• Our study adds a novel method to the diagnosis of PBD, which may also be of benefit for future neonatal mass screening programs based on acylcarnitine profiling [26].

References