Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease
Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease
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DOI：
10.1073/pnas.95.15.8630
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发表时间：
1998-07-21
影响因子：
11.1
通讯作者：
Gould, SJ
中科院分区：
文献类型：
--
作者：
Geisbrecht, BV;Collins, CS;Gould, SJ
过氧化物酶体基质蛋白的输入需要两个AAA ATP酶的作用，PEX1和PEX6。PEX1或PEX6基因的突变是致死性神经系统疾病Zellweger综合征、新生儿肾上腺脑白质营养不良和婴儿Refsum病的最常见原因，并且占所有此类患者的80%。我们在此报告，PEX6的过表达可以抑制某些PEX1缺陷细胞的表型，PEX1的过表达可以抑制某些PEX6缺陷细胞的表型，并且这些抑制的情况是等位基因特异性的，并且需要突变基因的部分活性。除了PEX1和PEX6之间相互作用的遗传证据之外，我们发现PEX1和PEX6蛋白在酵母双杂交测定中相互作用并且在体外彼此物理缔合。我们先前鉴定了PEX1中的错义突变G843D，其减弱PEX1功能并且是这些疾病的最常见原因，存在于所有此类患者的三分之一中。G843D突变减弱了PEX1和PEX6在双杂交系统和体外两者中的相互作用，并且似乎被PEX6的过表达抑制。我们的结论是，PEX1和PEX6形成一个复杂的过氧化物酶体生物合成的核心重要性，影响这个复杂的突变构成的齐薇格综合征疾病谱的最常见的原因。
Peroxisomal matrix protein import requires the action of two AAA ATPases, PEX1 and PEX6. Mutations in either the PEX1 or PEX6 gene are the most common cause of the lethal neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease and account for disease in 80% of all such patients, We report here that overexpression of PEX6 can suppress the phenotypes of certain PEX1-deficient cells, that overexpression of PEX1 can suppress the phenotypes of certain PEX6-deficient cells, and that these instances of suppression are allele-specific and require partial activity of the mutated gene, In addition to genetic evidence for interaction between PEX1 and PEX6, we find that the PEX1 and PEX6 proteins interact in the yeast two-hybrid assay and physically associate with one another in vitro. We previously identified a missense mutation in PEX1, G843D, which attenuates PEX1 function and is the most common cause of these diseases, present in one-third of all such patients, The G843D mutation attenuates the interaction between PEX1 and PEX6 in both the two-hybrid system and in vitro and appears to be suppressed by overexpression of PEX6. We conclude that PEX1 and PEX6 form a complex of central importance to peroxisome biogenesis and that mutations affecting this complex constitute the most common cause of the Zellweger syndrome spectrum of diseases.