Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency

作者：Hanlu Wang, Dan‐dan Ruan, Min Wu, Yuanyuan Ji, Xingxing Hu, Qiuyan Wu, Yanping Zhang, Bin Lin, Yanan Hu, Hang Wang, Yi Tang, Zhu-ting Fang, Jie-wei Luo, Lisheng Liao, Mei-zhu Gao · 发表于：Thrombosis Journal · 年份：2023 · DOI：10.1186/s12959-022-00443-6 · 被引用次数：14 · 研究领域：Blood Coagulation and Thrombosis Mechanisms、Protease and Inhibitor Mechanisms、Genomics and Rare Diseases

BACKGROUND: Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. METHODS: Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. RESULTS: The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discov...