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Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York 10021
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.
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