Molecular basis of SERPINC1 mutations in Japanese patients with antithrombin deficiency. Issue 178 (June 2019)

• Record Type: Journal Article
• Authors: Tamura, Shogo; Hashimoto, Erika; Suzuki, Nobuaki; Kakihara, Misaki; Odaira, Koya; Hattori, Yuna; Tokoro, Mahiru; Suzuki, Sachiko; Takagi, Akira; Katsumi, Akira; Hayakawa, Fumihiko; Suzuki, Atsuo; Okamoto, Shuichi; Kanematsu, Takeshi; Matsushita, Tadashi; Kojima, Tetsuhito
• Is Part Of: Thrombosis research. Issue 178(2019)
• Page Start: 159
• Page End: 170
• Publication Date: 2019-06
• Subjects: Antithrombin deficiency -- Genetic mutation -- Gene rearrangement -- SERPINC1 -- Thrombosis; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2019.04.004
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Background: Congenital antithrombin (AT) deficiency, which arises from various SERPINC1 defects, is an autosomal-dominant thrombophilic disorder associated with a high risk of recurrent venous thromboembolism. Patients/methods: We investigated SERPINC1 defects in Japanese patients with congenital AT deficiency who developed venous thromboembolism or had a family history of deep vein thrombosis. We analyzed the full DNA sequences of SERPINC1 exons and exon-intron junctions by PCR-mediated direct sequencing. If no mutation was found, multiplex ligation-dependent probe amplification (MLPA) was conducted for the relative quantification of the copy number of all exons in SERPINC1 . If splice-site mutations were detected, mRNA splicing abnormalities were further investigated using an in vitro cell-based exontrap assay. Results: We identified 19 different SERPINC1 abnormalities, including 8 novel mutations, in 21 Japanese patients with AT deficiency. These abnormalities were distributed as follows: 9 missense mutations (42.9%), 3 nonsense mutations (14.3%), 1 splice-site mutation (4.8%), 2 small insertions (9.5%), 2 deletion mutations (9.5%) and 4 large deletions (19.0%). Cases with large deletions of SERPINC1 included Alu -mediated gene rearrangements and non- Alu -mediated complex gene rearrangements; the latter could conceivably be explained using the fork stalling and template switching (FoSTeS) model. Conclusions: We identified a variety of SERPINC1 defects in Japanese patients with AT deficiency. The SERPINC1 mutations detected in patients with type I AT deficiency included single nucleotide missense or nonsense mutations, small intragenic insertions or deletions, and large genomic structural deletions. Large deletions of SERPINC1 were caused by various recurrent or non-recurrent complex genomic rearrangement mutations. Highlights: Congenital antithrombin deficiency is caused by various SERPINC1 abnormalities. We identified 8 novel SERPINC1 mutations in 21 Japanese antithrombin deficiencies. A unique genomic structural mutation in type I antithrombin deficiency was found. Deletions of SERPINC1 were due to recurrent or non-recurrent gene rearrangements.