Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder.
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.
Faust
P L
PL
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York 10021, USA. plf3@columbia.edu
Hatten
M E
ME
D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology*; D002465:Cell Movement; D002531:Cerebellum / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000737:chemistry; D005227:Fatty Acids / Q000097:blood; D008099:Liver / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008830:Microbodies / Q000235:genetics*; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D009474:Neurons; D000074428:Peroxisomal Biogenesis Factor 2; D010955:Plasmalogens / Q000032:analysis; D012886:Skull / Q000473:pathology; D015211:Zellweger Syndrome / Q000235:genetics*
D005227:Fatty Acids; D008565:Membrane Proteins; C000614230:PEX2 protein, human; C000614231:PEX2 protein, mouse; D010955:Plasmalogens; D000074428:Peroxisomal Biogenesis Factor 2