Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia.
Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia.
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DOI：
10.1371/journal.pone.0026206
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Al-Gazali L
中科院分区：
文献类型：
--
作者：
Ali BR;Ben-Rebeh I;John A;Akawi NA;Milhem RM;Al-Shehhi NA;Al-Ameri MM;Al-Shamisi SA;Al-Gazali L
遗传性出血性毛细血管扩张症（HHT）是一种影响血管系统的常染色体显性遗传疾病，其特征为鼻衄、动静脉畸形以及粘膜皮肤和胃肠道毛细血管扩张。这种疾病影响全世界约8,000人中的1人。在受影响的个体中，显著的发病率与这种病症相关，并且贫血可能是肠道和鼻子中毛细血管扩张反复出血的结果。在报告的大多数病例中，这种情况是由ACVRL 1或endoglin基因突变引起的，这些基因编码TGF-β信号通路的组分。许多错义突变的endoglin已被报道为致病缺陷的HHT，但这些突变引起的确切的潜在的细胞机制尚未完全建立，尽管数据支持内质网（ER）的质量控制机制的作用。出于这个原因，我们研究了25个导致内皮糖蛋白疾病的错义突变的亚细胞运输。突变蛋白在HeLa和HEK 293细胞系中表达，并且通过共聚焦荧光显微镜以及其N-糖基化谱的分析建立其亚细胞定位。ER质量控制被认为是负责八个（L32 R，V49 F，C53 R，V125 D，A160 D，P165 L，I271 N和A308 D）的11个突变体位于孤儿细胞外结构域除了两个（C363 Y和C382 W）的13个突变体中的透明带（ZP）域。此外，一个单一的细胞内结构域的错义突变体进行了检查，发现交通主要是质膜。这些研究结果支持的概念，参与ER的质量控制的机制，一个显着的数字，但不是所有的，错义内皮糖蛋白突变体中发现的HHT 1型患者。其他机制包括与信号伴侣相互作用的丧失以及对功能残基的不利影响可能是突变蛋白功能丧失的原因。
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER) quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D) out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W) out of thirteen mutants in the Zona Pellucida (ZP) domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional residues are likely to be the cause of the mutant proteins' loss of function.