title: Molecular basis of inherited antithrombin deficiency in Portuguese families: identification of genetic alterations and screening for additional thrombotic risk factors.
abstract: Antithrombin (AT), the most important coagulation serine proteases inhibitor, plays an important role in maintaining the hemostatic balance. Inherited AT deficiency, mainly characterized by predisposition to recurrent venous thromboembolism, is transmitted in an autosomal dominant manner. In this study, we analyzed the underlying genetic alterations in 12 unrelated Portuguese thrombophilic families with AT deficiency. At the same time, the modulating effect of the FV Leiden mutation, PT 20210A, PAI-1 4G, and MTHFR 677T allelic variants, on the thrombotic risk of AT deficient patients was also evaluated. Three novel frameshift alterations, a 4-bp deletion in exon 4 and two 1-bp insertions in exon 6, were identified in six unrelated type I AT deficient families. A novel missense mutation in exon 3a, which changes the highly conserved F147 residue, and a novel splice site mutation in the invariant acceptor AG dinucleotide of intron 2 were also identified in unrelated type I AT deficient families. In addition to these, two previously reported missense mutations changing the AT reactive site bond (R393-S394) and leading to type II-RS deficiency, and a previously reported cryptic splice site mutation (IVS4-14G-->A), were also identified. In these families, increased thrombotic risk associated with co-inheritance of the FV Leiden mutation and of the PAI-1 4G variant was also observed. In conclusion, we present the first data regarding the underlying genetic alterations in Portuguese thrombophilic families with AT deficiency, and confirm that the FV Leiden mutation and probably the PAI-1 4G variant represent additional thrombotic risk factors in these families.
authors.affiliation: Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal. dezso.david@insa.min-saude.pt
authors.forename: Dezsö
authors.initials: D
authors.lastname: David
authors.forename: Sofia
authors.initials: S
authors.lastname: Ribeiro
authors.forename: Lénia
authors.initials: L
authors.lastname: Ferrão
authors.forename: Teresa
authors.initials: T
authors.lastname: Gago
authors.forename: Francisco
authors.initials: F
authors.lastname: Crespo
mesh_terms: D000595:Amino Acid Sequence; D000991:Antithrombins / Q000172:deficiency* / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005190:Family; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D011174:Portugal; D012307:Risk Factors; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013927:Thrombosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D000991:Antithrombins; D017931:DNA Primers