title: Molecular basis of type I antithrombin deficiency in two women with recurrent venous thromboembolism in the first trimester of pregnancy.
abstract: Inherited antithrombin (AT) deficiency carries a 50% risk of venous thromboembolism (VTE) during pregnancy. Here, we investigated the molecular basis of type I AT deficiency in two women with recurrent VTE in the first trimester of pregnancy. Phenotype analysis showed both probands had almost 50% of normal AT levels. Two novel heterozygous AT mutations were identified: g.7920C>T resulting in a Trp225Cys mutation in case 1 and g.13863C>A causing an Ala404Asp mutation in case 2. Transient expression of either wild-type (WT) or mutant AT expression vectors in HEK293T and CHO cells showed impaired secretion of both AT mutant proteins. Immunofluorescence analysis revealed that the staining of AT-Trp225Cys in both endoplasmic reticulum (ER) and Golgi apparatus was similar to that of AT-WT, and the staining of AT-Ala404Asp was mainly present in ER but was weaker than that of AT-WT. These results revealed that the type I AT deficiency in two patients was caused by impaired secretion of the AT-Trp225Cys and AT-Ala404Asp mutant proteins, respectively. The two mutations are associated with a high risk of thrombotic onset and women with these AT mutations are prone to VTE in early pregnancy.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Qiu-Ya
authors.initials: QY
authors.lastname: Lu
authors.forename: Ye-Ling
authors.initials: YL
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Dai
authors.forename: Qiu-Lan
authors.initials: QL
authors.lastname: Ding
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Xi
authors.forename: Hong-Li
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000328:Adult; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D002460:Cell Line; D005260:Female; D005838:Genotype; D006801:Humans; D009154:Mutation; D010375:Pedigree; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000235:genetics*; D011261:Pregnancy Trimester, First; D012307:Risk Factors; D054556:Venous Thromboembolism / Q000209:etiology*
chemical_list: D000990:Antithrombin III