Targeted Deletion of the PEX2 Peroxisome Assembly Gene in Mice Provides a Model for Zellweger Syndrome, a Human Neuronal Migration Disorder

Targeted Deletion of the PEX2 Peroxisome Assembly Gene in Mice Provides a Model for Zellweger... Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2 -deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2 -deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar–lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease. Footnotes Address all correspondence to Phyllis Faust, Department of Pathology, Columbia University, PH Stem 15-124, 630 West 168th Street, New York, NY 10032. Tel.: (212) 305-7339. Fax: (212) 305-4548. E-mail: plf3@columbia.edu Abbreviations used in this paper: BLBP brain lipid binding protein ES embryonic stem PBD peroxisome biogenesis disorder PC Purkinje cell PTS peroxisomal targeting signal VLCFA very long chain fatty acids Submitted: 28 July 1997 Revision received 16 September 1997 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

Targeted Deletion of the PEX2 Peroxisome Assembly Gene in Mice Provides a Model for Zellweger Syndrome, a Human Neuronal Migration Disorder

The Journal of Cell Biology, Volume 139 (5): 1293 – Dec 1, 1997

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Publisher
Rockefeller University Press
Copyright
© 1997 Rockefeller University Press
ISSN
0021-9525
eISSN
1540-8140
DOI
10.1083/jcb.139.5.1293
Publisher site
See Article on Publisher Site

Abstract

Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2 -deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2 -deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar–lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease. Footnotes Address all correspondence to Phyllis Faust, Department of Pathology, Columbia University, PH Stem 15-124, 630 West 168th Street, New York, NY 10032. Tel.: (212) 305-7339. Fax: (212) 305-4548. E-mail: plf3@columbia.edu Abbreviations used in this paper: BLBP brain lipid binding protein ES embryonic stem PBD peroxisome biogenesis disorder PC Purkinje cell PTS peroxisomal targeting signal VLCFA very long chain fatty acids Submitted: 28 July 1997 Revision received 16 September 1997

Journal

The Journal of Cell BiologyRockefeller University Press

Published: Dec 1, 1997

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