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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human PEX9: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly
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Human PEX9: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly

机译：人PEX9：通过功能互补进行cDNA克隆，Zellweger综合征患者的突变分析以及过氧化物酶体膜组装中的潜在作用

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摘要

At least 11 complementation groups (CGs) have been identified for the peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome, for which seven pathogenic genes have been elucidated. We have isolated a human M9 cDNA (N9) by functional complemcntation of peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZPl19, defective in import of both matrix and membrane proteins. This cDNA encodes a hydrophilic protein (Pex19p) comprising 299 amino acids, with a prenylation motif, CAAX box, at the C terminus. Farnesylated Pex19p is partly, if not all, anchored in the peroxisomal membrane, exposing its N-terminal Part to the cytosol. A stable transformant of ZP119 with HsPEX19 was morphologically and biochemically restored for peroxisome biogenesis. HsPEX9 expression also restored peroxisomal protein import in fibroblasts from a patient (PBDJ-01) with Zelboger syndrome of CG-J. This patient (PBDJ-01) possessed a homozygous, inactivating mutation: a 1-base insertion, A764, in a codon for Me255, resulted in a frameshift, inducing a 24-aa sequence entirely distinct from normal Pex19p. These results demonstrate that PEX9 is the causative gene for CG-J PBD and suggest that the C-terminal part, including the CAAX homology box, is required for the biological function of Pcx19p. Morcover, Pex19p is apparently involved at the initial stage in peroxisome mem- branc assembly, before the import of matrix protein.
机译：对于过氧化物酶体生物发生障碍（PBD），例如Zellweger综合征，已鉴定出至少11个互补组（CG），已阐明了七个致病基因。我们已经通过突变中国仓鼠卵巢细胞系ZP1919的过氧化物酶体缺乏症的功能增强分离了人M9 cDNA（N9），其在基质和膜蛋白的导入方面均存在缺陷。此cDNA编码一个亲水蛋白（Pex19p），该蛋白包含299个氨基酸，在C端带有异戊烯基化基序CAAX box。法尼基化的Pex19p部分（如果不是全部）锚定在过氧化物酶体膜中，使其N末端部分暴露于胞质溶胶。用过氧化物酶体生物发生在形态和生化上恢复了具有HsPEX19的ZP119的稳定转化体。 HsPEX9表达还恢复了患有CG-J Zelboger综合征的患者（PBDJ-01）的成纤维细胞中过氧化物酶体蛋白的导入。该患者（PBDJ-01）具有纯合的失活突变：Me255密码子中的1个碱基插入A764，导致移码，并诱导了与正常Pex19p完全不同的24-aa序列。这些结果表明，PEX9是CG-J PBD的致病基因，表明Pcx19p的生物学功能需要C末端部分（包括CAAX同源框）。 Morcover，Pex19p显然是在过氧化物酶体膜组装的初始阶段，然后才引入基质蛋白。

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