Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation
Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation
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DOI：
10.1086/377004
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发表时间：
2003-08-01
影响因子：
9.8
通讯作者：
Fujiki, Y
中科院分区：
文献类型：
--
作者：
Matsumoto, N;Tamura, S;Fujiki, Y
人类的过氧化物酶体生物发生障碍(PBDS)被细分为12个互补组(CGs)。CG8是其中较常见的一种，与不同的表型有关，从最严重的Zellweger综合征(ZS)到较轻的新生儿肾上腺脑白质营养不良(Nald)和婴儿Refsum病(IRD)。编码305个氨基酸的膜过氧化物素的PEX26在CG8中缺失。我们研究了8例CG8患者成纤维细胞中的PEX26基因，其中4例为ZS表型，2例为NALD，2例为IRD。在所有这些细胞系中，过氧化氢酶大多是胞浆的，但含有SKL过氧化物酶体靶向序列PTS1的蛋白质的进口是正常的。PEX26在所有8个细胞系中重新建立的过氧化物体的表达，证实了PEX26缺陷在CG8患者中是致病的。当细胞在30℃培养时，Nald和IRD表型患者的细胞株中过氧化氢酶进口恢复，但在ZS表型患者中恢复的程度要小得多，这表明温度敏感性与临床表型的严重程度成反比。发现了几种类型的突变，包括两名ZS患者的G89R纯合子突变。这些PEX26突变在pex26中国仓鼠卵巢细胞中的表达导致了与人类细胞系相似的细胞表型。这些发现证实，pex26细胞系的温度敏感性程度可以预测PEX26缺乏症患者的临床表型。
The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups (CGs). CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). PEX26, encoding the 305-amino-acid membrane peroxin, has been shown to be deficient in CG8. We studied the PEX26 genotype in fibroblasts of eight CG8 patients - four with the ZS phenotype, two with NALD, and two with IRD. Catalase was mostly cytosolic in all these cell lines, but import of the proteins that contained PTS1, the SKL peroxisome targeting sequence, was normal. Expression of PEX26 reestablished peroxisomes in all eight cell lines, confirming that PEX26 defects are pathogenic in CG8 patients. When cells were cultured at 30 degreesC, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype. Several types of mutations were identified, including homozygous G89R mutations in two patients with ZS. Expression of these PEX26 mutations in pex26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines. These findings confirm that the degree of temperature sensitivity in pex26 cell lines is predictive of the clinical phenotype in patients with PEX26 deficiency.