Research Papers:

A small deletion in SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum stress

Jingjing Su, Liang Shu, Zhou Zhang, Lei Cai, Xin Zhang, Yu Zhai and Jianren Liu _

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Oncotarget. 2016; 7:76882-76890. https://doi.org/10.18632/oncotarget.12349

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Jingjing Su1,*, Liang Shu1,*, Zhou Zhang2,*, Lei Cai3, Xin Zhang1, Yu Zhai1, Jianren Liu1,4

1Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

2Institute of Biliary Tract Disease Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

3Bio-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

4Clinical Research Center of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

*These authors have contributed equally to this work as co-first authors

Correspondence to:

Jianren Liu, email: [email protected]

Yu Zhai, email: [email protected]

Keywords: SERPINC1, deletion mutation, antithrombin deficiency, endoplasmic reticulum stress

Received: April 23, 2016     Accepted: September 20, 2016     Published: September 30, 2016


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.

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