A small deletion in SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum stress.
A small deletion in SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum stress.
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SERPINC1 的小缺失通过促进内质网应激导致 I 型抗凝血酶缺乏
DOI：
10.18632/oncotarget.12349
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Su J;Shu L;Zhang Z;Cai L;Zhang X;Zhai Y;Liu J
抗凝血酶（AT）缺乏症是一种常染色体显性遗传疾病，突变AT变体的鉴定将提高我们对这种丝氨酸蛋白酶抑制剂（SERPIN）的抗凝功能和这种疾病的分子途径的理解。在本研究中，我们进行了全外显子测序的中国家庭深静脉血栓形成，并确定了一个新的小缺失，消除4个氨基酸（INEL）的SERPINC1基因外显子4。这通过增强这种蛋白质的细胞内滞留而导致I型AT缺乏。AT滞留导致内质网（ER）应激，其进一步抑制AT释放。此外，ER应激激活ER相关降解，这促进AT降解。抑制ER应激增强AT的分泌，而抑制ER相关的降解抑制AT的释放。因此，我们的研究确定了一个新的突变（INEL缺失）引起的I型AT缺乏症，并揭示了一个新的机制，AT保留通过增强ER应激，这可能提供一个创新的方法来治疗AT缺乏症。
Antithrombin (AT) deficiency is an autosomal dominant disorder, and identification of mutation AT variants would improve our understanding of the anticoagulant function of this serine protease inhibitor (SERPIN) and the molecular pathways underlying this disorder. In the present study, we performed whole-exome sequencing of a Chinese family with deep vein thrombosis, and identified a new small deletion that eliminates four amino acids (INEL) from exon 4 of SERPINC1 gene. This causes type I AT deficiency by enhancing the intracellular retention of this protein. AT retention leads to endoplasmic reticulum (ER) stress, which further inhibits AT release. In addition, ER stress activates ER-associated degradation, which promotes AT degradation. Suppression of ER stress enhanced the secretion of AT, while inhibition of ER-associated degradation suppressed AT release. Thus, our study identified a new mutation (INEL deletion) causing type I AT deficiency, and uncovered a novel mechanism for AT retention through enhanced ER stress, which may provide an innovative approach for treating AT deficiency.