Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders

Peroxisome biogenesis disorders (PBDs) are severe autosomal recessive neuro logical diseases caused by a defect of peroxisomal assembly factors. Zellwe ger syndrome, the most severe phenotype, is characterized by hypotonia, psy chomotor retardation and neuronal migration disorder. Neonatal adrenoleukod ystrophy and infantile Refsum disease are milder phenotypes of this disease . Thirteen complementation groups have been established since the genetic h eterogeneity of PBDs was elucidated in 1988. Eleven genes for PBDs have bee n identified either by a functional complementation cloning or by EST homol ogy searches. In 1992, the first gene for PBDs, PEX2, was identified. It en codes peroxisomal integral membrane protein with a RING finger domain. PEX5 and PEX7 are the genes for peroxisomal targeting signal (PTS)-1 and -2 rec eptors, respectively. PEX3, PEX16 and PEX19 are considered to be required f or the early stage of peroxisome biogenesis. PEX13 protein has an SH3 docki ng site that binds to the PTS-1 receptor. PEX1 and PEX6 encode ABC protein, and PEX10 and PEX12 also encode integral membrane protein, with RING finge r. Temperature-sensitivity, whereby peroxisomal biogenesis and metabolic dy sfunctions are restored at 30 degreesC in cells from mild phenotypes, is a useful event for predicting the clinical severity and for elucidation of pe roxisome biogenesis. Investigations using knockout mice are expected to fac ilitate understanding of migration disorders.