title: Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype.
abstract: Zellweger syndrome is the archetypical peroxisome biogenesis disorder and is characterized by defective import of proteins into the peroxisome, leading to peroxisomal metabolic dysfunction and widespread tissue pathology. In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype. To develop mouse models for this disorder, we have generated a targeted mouse with a loxP-modified Pex13 gene to enable conditional Cre recombinase-mediated inactivation of Pex13. In the studies reported here, we crossed these mice with transgenic mice that express Cre recombinase in all cells to generate progeny with ubiquitous disruption of Pex13. The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals. Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis. The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect. Thus, Pex13(-/-) mice reproduce many of the features of Zellweger syndrome and PEX13 deficiency in humans.
authors.affiliation: School of Biomolecular and Biomedical Science, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
authors.forename: Megan
authors.initials: M
authors.lastname: Maxwell
authors.forename: Jonas
authors.initials: J
authors.lastname: Bjorkman
authors.forename: Tam
authors.initials: T
authors.lastname: Nguyen
authors.forename: Peter
authors.initials: P
authors.lastname: Sharp
authors.forename: John
authors.initials: J
authors.lastname: Finnie
authors.forename: Carol
authors.initials: C
authors.lastname: Paterson
authors.forename: Ian
authors.initials: I
authors.lastname: Tonks
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Paton
authors.forename: Graham F
authors.initials: GF
authors.lastname: Kay
authors.forename: Denis I
authors.initials: DI
authors.lastname: Crane
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002465:Cell Movement; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000378:metabolism; D015211:Zellweger Syndrome / Q000235:genetics*
chemical_list: D008164:Luminescent Proteins; D008565:Membrane Proteins; C491106:Pex13 protein, mouse; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases