title: Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders.
abstract: Peroxisome biogenesis disorders (PBD) comprise three phenotypes including Zellweger syndrome (ZS) (the most severe), neonatal adrenoleucodystrophy, and infantile Refsum disease (IRD) (the most mild), and can be classified into at least 12 genetic complementation groups, which are not predictive of the phenotypes. Several pathogenic genes for PBD groups have been identified, but the relationship between the defective gene products and phenotypic heterogeneity has remained unclear. We identified a mutation in the PEX2 gene in an IRD patient with compound heterozygosity for a missense mutation and the known nonsense mutation detected in ZS patients. In transfection experiments using the peroxisome deficient CHO mutant, Z65 with a nonsense mutation in the PEX2 gene, we noted the E55K mutation had mosaic activities of peroxisomal protein import machinery and residual activities of peroxisomal functions, including dihydroxyacetone phosphate acyltransferase and beta oxidation of very long chain fatty acids. The nonsense mutation severely affects these peroxisomal functions as well as the protein import. These data suggest that allelic heterogeneity of the PEX gene affects the peroxisomal protein import and functions and regulates the clinical severity in PBD.
authors.affiliation: Department of Paediatrics, Gifu University School of Medicine, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shimozawa
authors.forename: A
authors.initials: A
authors.lastname: Imamura
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Orii
authors.forename: T
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: T
authors.initials: T
authors.lastname: Osumi
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiki
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: G
authors.initials: G
authors.lastname: Besley
authors.forename: N
authors.initials: N
authors.lastname: Kondo
mesh_terms: D002374:Catalase / Q000378:metabolism; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D000074428:Peroxisomal Biogenesis Factor 2; D018901:Peroxisomal Disorders / Q000235:genetics*; D010641:Phenotype; D013696:Temperature; D014162:Transfection; D015211:Zellweger Syndrome / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C000614230:PEX2 protein, human; D000074428:Peroxisomal Biogenesis Factor 2; D002374:Catalase