| Research Abstract |
With the support of this Grants-in Aid for Scientific Research 11680608, we obtained following findings :
The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), are fatal autosomal recessive diseases caused by defects in peroxisome assembly as well as malfunction of peroxisomes, where 12 genotypes have been reported. ZS patients manifest the severest clinical and biochemical abnormalities, while those with NALD and IRD show the less severity and the mildest features, respectively. However, little attention has been paid to determining at the molecular level the phenotype-genotype relationships for the variable severity in clinical features between the severest ZS, NALD, and the mildest, IRD.
We have isolated a human PEX1 cDNA (HsPEX1) by functional complementation of peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP107. PEX1 is the causative gene for PBDs of complementa
… More
tion group E (CG-E ; CG1 in USA/EU), the highest incidence PBD, and encodes the peroxin, Pex1p, a member of AAA-ATPase protein family. We earlier reported that temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD.It has been also reported that Pex1p and Pex6p interact with each other. In the present work, we investigated phenotype-genotype relationships of CG1 PBDs. Pex1p from IRD such as Pex1p with the frequently identified G843D was mostly degraded in vivo at 37℃, while it was detectable at a normal level in permissive temperature, 30℃. In contrast, Pex1p from ZS patients-derived PEX proteins, including each with a mutation at L664P or a deletion of amino acid residues at 634-690 were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at 50% level of normal Pex1p, whilst Pex1p from ZS patients showing non-temperature-sensitive peroxisome biogenesis barely bound to Pex6p. Taken together, it is most likely that the stability of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities notable in ZS. Less
|
