Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene.
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.
Picard
Véronique
V
Service d'hématologie Biologique A, Hôpital Européen Georges Pompidou, Paris, France. veronique.picard@cep.u-psud.fr
Nowak-Göttl
Ulrike
U
Biron-Andreani
Christine
C
Fouassier
Marc
M
Frere
Corinne
C
Goualt-Heilman
Michèle
M
de Maistre
Emmanuel
E
Regina
Sandra
S
Rugeri
Lucia
L
Ternisien
Catherine
C
Trichet
Catherine
C
Vergnes
Christine
C
Aiach
Martine
M
Alhenc-Gelas
Martine
M
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
D000990:Antithrombin III