Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype

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dc.contributor.authorMaxwell, M.
dc.contributor.authorBjorkman, J.
dc.contributor.authorNguyen, T.
dc.contributor.authorSharp, P.
dc.contributor.authorFinnie, J.
dc.contributor.authorPaterson, C.
dc.contributor.authorTonks, I.
dc.contributor.authorPaton, B.
dc.contributor.authorKay, G.
dc.contributor.authorCrane, D.
dc.date.issued2003
dc.description.abstractZellweger 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.
dc.description.statementofresponsibilityMegan Maxwell, Jonas Bjorkman, Tam Nguyen, Peter Sharp, John Finnie, Carol Paterson, Ian Tonks, Barbara C. Paton, Graham F. Kay, and Denis I. Crane
dc.identifier.citationMolecular and Cellular Biology, 2003; 23(16):5947-5957
dc.identifier.doi10.1128/MCB.23.16.5947-5957.2003
dc.identifier.issn0270-7306
dc.identifier.issn1098-5549
dc.identifier.orcidFinnie, J. [0000-0003-2277-1693]
dc.identifier.urihttp://hdl.handle.net/2440/7691
dc.language.isoen
dc.publisherAmer Soc Microbiology
dc.source.urihttps://doi.org/10.1128/mcb.23.16.5947-5957.2003
dc.subjectLiver
dc.subjectCerebral Cortex
dc.subjectNeurons
dc.subjectPeroxisomes
dc.subjectFibroblasts
dc.subjectHepatocytes
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectMice, Knockout
dc.subjectMice
dc.subjectZellweger Syndrome
dc.subjectDisease Models, Animal
dc.subjectIntegrases
dc.subjectLuminescent Proteins
dc.subjectGreen Fluorescent Proteins
dc.subjectMembrane Proteins
dc.subjectViral Proteins
dc.subjectMicroscopy, Electron
dc.subjectMicroscopy, Fluorescence
dc.subjectBlotting, Western
dc.subjectBlotting, Northern
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectCell Movement
dc.subjectProtein Biosynthesis
dc.subjectTranscription, Genetic
dc.subjectBase Sequence
dc.subjectPhenotype
dc.subjectMutation
dc.subjectPlasmids
dc.subjectMolecular Sequence Data
dc.titlePex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype
dc.typeJournal article
pubs.publication-statusPublished

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