Open AccessA small deletion in SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum stress
Author(s) -
Jingjing Su,
Liang Shen,
Zhou Zhang,
Lei Cai,
Xin Zhang,
Zhengquan Yu,
Jian-Ren Liu
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.12349
Subject(s) - endoplasmic reticulum , unfolded protein response , serpin , mutation , exome sequencing , antithrombin , serine protease , biology , er retention , secretion , endocrinology , microbiology and biotechnology , chemistry , protease , gene , biochemistry , mutant , enzyme , heparin
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.