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Blood, 1 July 2004, Vol. 104, No. 1, pp. 128-134. Prepublished online as a Blood First Edition Paper on March 16, 2004; DOI 10.1182/blood-2003-10-3530. This Article Full Text (PDF) All Versions of this Article: 2003-10-3530v1 104/1/128    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 Kravtsov, D. V Articles by Gailani, D. Search for Related Content PubMed PubMed Citation Articles by Kravtsov, D. V Articles by Gailani, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 15, 2003 Accepted February 26, 2004 Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain Dmitri V Kravtsov, Wenman Wu, Joost C Meijers, Mao-Fu Sun, Morey A Blinder, Thao P Dang, Hongli Wang, and David Gailani* Pathology, Vanderbilt University, Nashville, TN, USA Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Second Medical University, Shanghai, China Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Medicine, Washington University School of Medicine, St. Louis, MO, USA Medicine, Vanderbilt University, Nashville, TN, USA Pathology, Vanderbilt University, Nashville, TN, USA; Medicine, Vanderbilt University, Nashville, TN, USA * Corresponding author; email: dave.gailani{at}vanderbilt.edu. The bleeding diathesis associated with hereditary factor XI (fXI) deficiency is prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal recessive condition. The homodimeric structure of fXI implies that the product of a single mutant allele could confer disease in a dominant manner through formation of heterodimers with wild type polypeptide. We studied two unrelated patients with fXI levels <20% of normal, and family histories indicating dominant disease transmission. Both are heterozygous for single amino acid substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither mutant is secreted by transfected fibroblasts. In co-transfection experiments with a wild type fXI construct, constructs with mutations common in Ashkenazi Jews (Glu117Stop and Phe283Leu), and a variant with a severe defect in dimer formation (fXI-Gly350Glu) have little effect on wild type fXI secretion. In contrast, co-transfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild type secretion ~50%, consistent with a dominant negative effect. Immunoprecipitation of cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data support a model in which non-secretable mutant fXI polypeptides trap wild type polypeptides within cells through heterodimer formation, resulting in lower plasma fXI levels than in heterozygotes for mutations that cause autosomal recessive fXI deficiency. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A new mechanism for inherited factor XI deficiency Uri Seligsohn Blood 2004 104: 7-8. [Full Text] [PDF] This article has been cited by other articles: G. Zadra, R. Asselta, M. L. Tenchini, G. Castaman, U. Seligsohn, P. M. Mannucci, and S. Duga Simultaneous genotyping of coagulation factor XI type II and type III mutations by multiplex real-time polymerase chain reaction to determine their prevalence in healthy and factor XI-deficient Italians Haematologica, May 1, 2008; 93(5): 715 - 721. [Abstract] [Full Text] [PDF] D. V. Kravtsov, P. E. Monahan, and D. Gailani A classification system for cross-reactive material-negative factor XI deficiency Blood, June 15, 2005; 105(12): 4671 - 4673. [Abstract] [Full Text] [PDF] M. Mitchell, L. Dai, G. Savidge, and A. Alhaq An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients Blood, October 15, 2004; 104(8): 2394 - 2396. [Abstract] [Full Text] [PDF] P. M. Mannucci, S. Duga, and F. Peyvandi Recessively inherited coagulation disorders Blood, September 1, 2004; 104(5): 1243 - 1252. [Abstract] [Full Text] [PDF]

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