title: Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene.
abstract: Antithrombin (AT) is a major physiological inhibitor of hemostasis. We report 22 novel antithrombin gene (SERPINC1) mutations associated with antithrombin deficiency in 17 French and five German families. They were all present at the heterozygous state. Nine missense mutations accounted for type I deficiency, defined by equally low antithrombin activity and antigen level. Most of them (7/9) affected highly conserved serpin residues and were associated with venous thrombosis occurring at a young age (before age 32). One splice site, one nonsense mutation, three small deletions and one insertion were also identified as a cause for type I antithrombin deficiency. Seven other missense mutations were identified in type II or unclassified AT deficiency; g.5270C>T (p.T147I, T115I) and g.5281A>T (p.I151F, I119F) change residues in the heparin binding region, g.13267C>G (p.P439A, P407A) and g.13271T>C (p.F440S, F408S) affect amino acids in the pleiotropic region, g.2372G>A (p.G25D, G-8D) changes a signal peptide amino acid, g.2456G>C (p.C53S, C21S) affects one of the three disulfide bonds of the protein, and g.7585A>T (p.M347K, M315K) changes a nonconserved residue on strand 2C.
authors.affiliation: Service d'hématologie Biologique A, Hôpital Européen Georges Pompidou, Paris, France. veronique.picard@cep.u-psud.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Picard
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
authors.forename: Christine
authors.initials: C
authors.lastname: Biron-Andreani
authors.forename: Marc
authors.initials: M
authors.lastname: Fouassier
authors.forename: Corinne
authors.initials: C
authors.lastname: Frere
authors.forename: Michèle
authors.initials: M
authors.lastname: Goualt-Heilman
authors.forename: Emmanuel
authors.initials: E
authors.lastname: de Maistre
authors.forename: Sandra
authors.initials: S
authors.lastname: Regina
authors.forename: Lucia
authors.initials: L
authors.lastname: Rugeri
authors.forename: Catherine
authors.initials: C
authors.lastname: Ternisien
authors.forename: Catherine
authors.initials: C
authors.lastname: Trichet
authors.forename: Christine
authors.initials: C
authors.lastname: Vergnes
authors.forename: Martine
authors.initials: M
authors.lastname: Aiach
authors.forename: Martine
authors.initials: M
authors.lastname: Alhenc-Gelas
mesh_terms: D000990:Antithrombin III / Q000737:chemistry / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005602:France; D005858:Germany; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010641:Phenotype; D012307:Risk Factors
chemical_list: D000990:Antithrombin III