A novel type 2A (Group II) von Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Willebrand factor multimers

Journal of Thrombosis and Haemostasis : JTH
Lee A O'BrienDavid Lillicrap

Abstract

Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF) associated with an absence of high-molecular-weight multimers. In this study, sequence analysis of the VWF gene from a Type 2A VWD patient showed a novel, heterozygous T-->A transversion at nucleotide 4510, resulting in the non-conservative substitution of L1503Q in the mature VWF subunit. This substitution, which was not found in 55 unrelated normal individuals, was reproduced by in vitro site directed mutagenesis of a full-length VWF cDNA and was subsequently expressed in COS-7 cells. The corresponding recombinant mutant VWF protein was partially retained in COS-7 cells yet the full spectrum of multimers was observed, suggesting that the absence of the highest molecular weight multimers results from increased proteolysis. The recombinant mutant VWF protein was digested with the ADAMTS13 protease from VWF-depleted plasma and the aberrant VWF multimer pattern was observed. These results suggest that the L1503Q substitution induces a conformational change in the VWF protein, which increases the protein's susceptibility to proteolysis. A three-dimensional model of the A2 domain demonstrates that the L1503Q...Continue Reading

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Citations

Jan 17, 2013·The Journal of Biological Chemistry·Amy J Xu, Timothy A Springer
Jan 18, 2006·Annual Review of Medicine·Han-Mou Tsai
Jul 5, 2005·Thrombosis Research·Paolo PerutelliAngelo C Molinari
Dec 19, 2006·Expert Review of Cardiovascular Therapy·Han-Mou Tsai
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Dec 3, 2005·Blood·Wolf Achim HassenpflugReinhard Schneppenheim
Nov 20, 2004·Journal of Thrombosis and Haemostasis : JTH·H-M Tsai
Feb 1, 2017·Hämostaseologie·Maria A Brehm
Mar 1, 2012·ASAIO Journal : a Peer-reviewed Journal of the American Society for Artificial Internal Organs·Han-Mou Tsai

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