Zellweger syndrome is a lethal
neurological disorder characterized by severe defects in peroxisomal
protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other
Zellweger syndrome phenotypes, including neuronal migration defects,
hypotonia, a developmental delay, and neonatal lethality. These phenotypes are also manifested in mouse models of
Zellweger syndrome generated by disruption of the PEX5 or PEX2 gene. Here we show that mice lacking peroxisomal
membrane protein PEX11 beta display several pathologic features shared by these mouse models of
Zellweger syndrome, including neuronal migration defects, enhanced neuronal apoptosis, a developmental delay,
hypotonia, and neonatal lethality. However, PEX11 beta deficiency differs significantly from
Zellweger syndrome and
Zellweger syndrome mice in that it is not characterized by a detectable defect in peroxisomal
protein import and displays only mild defects in peroxisomal
fatty acid beta-oxidation and peroxisomal
ether lipid biosynthesis. These results demonstrate that the neurological pathologic features of
Zellweger syndrome can occur without peroxisomal
enzyme mislocalization and challenge current models of
Zellweger syndrome pathogenesis.