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: Véronique Picard, Ulrike Nowak-Göttl, Christine Biron-Andreani, Marc Fouassier, Corinne Frere, Michèle Goualt-Heilman, Emmanuel de Maistre, Sandra Regina, Lucia Rugeri, Catherine Ternisien, Catherine Trichet, Christine Vergnes, Martine Aiach, Martine Alhenc-Gelas
• Journal: Human mutation (Hum Mutat) Vol. 27 Issue 6 Pg. 600 (Jun 2006) ISSN: 1098-1004 [Electronic] United States
• PMID: 16705712 (Publication Type: Journal Article)

Chemical References

• Antithrombin III

Topics

• Antithrombin III (chemistry, genetics)
• Antithrombin III Deficiency (classification, diagnosis, genetics)
• DNA Mutational Analysis
• Female
• France
• Germany
• Heterozygote
• Humans
• Mutation
• Phenotype
• Risk Factors