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 i n abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anoma lies associated with the disorders of peroxisome biogenesis remains un known. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly per oxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2-deficient mice survive in utero but die several hours after birt h. The mutant animals do not feed and are hypoactive and markedly hypo tonic. The PEX2-deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal b iochemical parameters, including accumulations of very long chain fatt y acids in plasma and deficient erythrocyte plasmalogens. Abnormal lip id storage is evident in the adrenal cortex, with characteristic lamel lar-lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an incr eased cell density in the underlying white matter, indicating an abnor mality of neuronal migration. These findings demonstrate that mice wit h a PEX2 gene deletion have a peroxisomal disorder and provide an impo rtant model to study the role of peroxisomal function in the pathogene sis of this human disease.