Studies on Perxisome Biogenesis and Function of Pex1p

在11680608的资助下，我们获得了以下研究结果：过氧化物酶体生物发生障碍（PBD），包括Zellweger综合征（ZS）和新生儿肾上腺脑白质营养不良（NALD）和婴儿Refsum病（IRD），是由过氧化物酶体组装缺陷以及过氧化物酶体功能障碍引起的致死性常染色体隐性遗传病，其中已报道了12种基因型。ZS患者表现出最严重的临床和生化异常，而NALD和IRD患者分别表现出较轻的严重程度和最温和的特征。然而，很少有人注意到在分子水平上确定的表型-基因型之间的关系的变量严重程度的临床特征之间的最严重的ZS，NALD，和最温和的，IRD.We已经分离出一个人PEX 1的cDNA（HsPEX 1）的功能互补的过氧化物酶体缺陷的突变中国仓鼠卵巢细胞系，ZP 107。PEX 1基因是补体系统PBD的致病基因， ...更多信息 E组（CG-E ;在美国/欧盟为CG 1）是PBD发病率最高的组，编码过氧化物酶，Pex 1 p，AAA-ATP酶蛋白家族成员。我们曾报道过温度敏感的过氧化物酶体组装是IRD临床特征温和的原因，也有报道Pex 1 p和Pex 6p相互作用。在本工作中，我们调查了CG 1 PBDs的表型-基因型关系。来自IRD的Pex 1 p，如常见的具有G843 D的Pex 1 p，在37℃下在体内大部分降解，而在允许温度30℃下可检测到正常水平。相比之下，来自ZS患者来源的PEX蛋白的Pex 1 p，包括在L 664 P处具有突变或在634-690处缺失氨基酸残基的每一种，在两种温度下稳定存在。Pex 1 p-G843 D以正常Pex 1 p的50%水平与Pex 6p相互作用，而来自显示非温度敏感性过氧化物酶体生物合成的ZS患者的Pex 1 p几乎不与Pex 6p结合。综上所述，Pex 1 p的稳定性很可能反映了IRD成纤维细胞中温度敏感的过氧化物酶体组装。Pex 1 p-Pex 6p相互作用的失败导致ZS中更严重的异常。少

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