[Human peroxisome-deficient disorders and pathogenic gene].

Peroxisome is a model organelle to investigate the mechanism of protein translocation and organelle assembly. Human autosomal recessive peroxisomal disorders are of clinical consequence and a model system to study the biogenesis and physiological significance of peroxisomes. In patients with generalized peroxisomal disease such as cerebrohepatorenal Zellweger syndrome where peroxisomes are morphologically absent, all peroxisomal proteins appear to be normally synthesized but assembly of peroxisomes is impaired. Thus far, nine complementation groups have been reported for these peroxisome-deficient disorders including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. To investigate the molecular mechanism of peroxisome biogenesis and the primary defect of peroxisomal disorders, we have thus far isolated three different complementation groups of Chinese hamster ovary (CHO) cell mutants defective in biogenesis of peroxisomes. By genetic functional complementation analysis following the transfection of cDNA library to one of these cell mutants, Z65, we identified 35-kDa peroxisome assembly factor-1 (PAF-1) essential for peroxisome assembly. Moreover, we delineated the primary defect in a Zellweger patient who belonged to the same complementation group as Z65. The cause of this syndrome was a homozygous nonsense point mutation at 119Arg in PAF-1 gene. Comparison of PAF-1 sequences from rat, human, and Chinese hamster revealed that PAF-1 is highly conserved through the evolution and contains a novel cysteine-rich zinc finger, RING finger motif.