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Prepublished online as a Blood First Edition Paper on February 20, 2003; DOI 10.1182/blood-2002-11-3391. This Article Full Text (PDF) All Versions of this Article: 2002-11-3391v1 102/3/919    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Picard, V. Articles by Aiach, M. Search for Related Content PubMed PubMed Citation Articles by Picard, V. Articles by Aiach, M. Social Bookmarking                   What's this? Submitted November 8, 2002 Accepted January 7, 2003 Antithrombin F229L: a new homozygous variant leading to spontaneous antithrombin polymerization in vivo associated with severe childhood thrombosis Veronique Picard*, Marie-Dominique Dautzenberg, Bruno O Villoutreix, Gilles Orliaguet, Martine Alhenc-Gelas, and Martine Aiach Service d Hematologie Biologique A, Hopital Europeen Georges Pompidou, Paris, France Laboratoire d Hematologie, UFR de Pharmacie, Universite Paris XI, Chatenay-Malabry, France Laboratoire d Hematologie, Hopital Necker-Enfants Malades, Paris, France Unite 428, INSERM, UFR de Pharmacie, Universite Paris V, Paris, France Departement d'anesthesie-reanimation, Hopital Necker-Enfants Malades, Paris, France * Corresponding author; email: veronique.picard{at}cep.u-psud.fr. There is increasing evidence that serpin conformational alteration caused by single point mutations can be responsible for protein deficiency associated with human diseases. A typical example is the 1-antitrypsin deficiency caused by the Z variant carrying a E342K substitution. Only few cases of 'conformational disease' involving other serpins are described so far. We investigated a severe antithrombin deficiency in a 13-month-old child with fever and cerebral venous thrombosis. The infant was found to be homozygous for a new antithrombin gene mutation (T to C at nt 7396, predicting an F229L antithrombin variant), and heterozygous for the FV Leiden mutation. Mild atypical antithrombin deficiency was found in both parents, who were first cousins, asymptomatic, and heterozygous for the same antithrombin gene mutation. The F229L variant, which does not readily fit into the current classification of antithrombin deficiency, was shown to be a thermolabile antithrombin that spontaneously polymerized in the proband's circulation. This points to a key role for the conserved Phe at position 229, which is near the reactive site loop in a region critical for serpin function and stability. Molecular modelling suggested how the mutation might destabilize this region of the protein and thereby favor reactive site loop insertion and polymerisation. This study provides the first direct evidence that antithrombin polymerization in vivo can cause antithrombin deficiency and severe thrombotic disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Gooptu and D. A. Lomas Polymers and inflammation: disease mechanisms of the serpinopathies J. Exp. Med., July 7, 2008; 205(7): 1529 - 1534. [Abstract] [Full Text] [PDF] F. Heidel, F. K. Solem, F. Breitenbuecher, D. B. Lipka, S. Kasper, M. H. Thiede, C. Brandts, H. Serve, J. Roesel, F. Giles, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Blood, January 1, 2006; 107(1): 293 - 300. [Abstract] [Full Text] [PDF]

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