title: A small deletion in SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum stress.
abstract: 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.
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shu
authors.affiliation: Institute of Biliary Tract Disease Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No.13dz2260500), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.|Clinical Research Center of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Jianren
authors.initials: J
authors.lastname: Liu
mesh_terms: D000990:Antithrombin III / Q000737:chemistry / Q000235:genetics*; D002681:China; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005337:Fibrin / Q000737:chemistry / Q000172:deficiency*; D006801:Humans; D008297:Male; D010375:Pedigree; D017384:Sequence Deletion; D020246:Venous Thrombosis / Q000235:genetics*; D000073359:Exome Sequencing
chemical_list: C542513:SERPINC1 protein, human; D000990:Antithrombin III; D005337:Fibrin
keywords: SERPINC1; antithrombin deficiency; deletion mutation; endoplasmic reticulum stress