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Molecular and Cellular Biology, August 2003, p. 5947-5957, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5947-5957.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pex13 Inactivation in the Mouse Disrupts Peroxisome Biogenesis and Leads to a Zellweger Syndrome Phenotype

Megan Maxwell,¹ Jonas Bjorkman,¹ Tam Nguyen,¹ Peter Sharp,² John Finnie,³ Carol Paterson,⁴ Ian Tonks,⁴ Barbara C. Paton,^2,5 Graham F. Kay,⁴ and Denis I. Crane^1*

School of Biomolecular and Biomedical Science, Griffith University, Nathan, Brisbane, Queensland 4111,¹ Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, South Australia 5006,² Institute of Medical and Veterinary Science, Adelaide, South Australia 5000,³ Queensland Institute of Medical Research, Brisbane, Queensland 4029,⁴ Department of Pediatrics, University of Adelaide, Adelaide, South Australia 5005, Australia⁵

Received 9 December 2002/ Returned for modification 14 April 2003/ Accepted 19 May 2003

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.

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* Corresponding author. Mailing address: School of Biomolecular and Biomedical Science, Griffith University, Nathan, Brisbane, Queensland 4111, Australia. Phone: 61-7 3875 7253. Fax: 61-7 3875 7773. E-mail: d.crane{at}griffith.edu.au.

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Molecular and Cellular Biology, August 2003, p. 5947-5957, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5947-5957.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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