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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3468-3478. Prepublished online as a Blood First Edition Paper on January 9, 2008; DOI 10.1182/blood-2007-08-108068. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2007-08-108068v1 111/7/3468    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Venceslá, A. Articles by Tizzano, E. F. Search for Related Content PubMed PubMed Citation Articles by Venceslá, A. Articles by Tizzano, E. F. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites Adoración Venceslá1, María Ángeles Corral-Rodríguez2, Manel Baena1, Mónica Cornet1, Montserrat Domènech1, Montserrat Baiget1, Pablo Fuentes-Prior2, and Eduardo F. Tizzano1 1 Department of Genetics and Centro de Investigación Biomédica en Red de Enfermadades Raras Instituto de Salud Carlos III and 2 Cardiovascular Research Center, Spanish National Research Council-Catalan Institute of Cardiovascular Sciences, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapiFIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020