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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-12-3693.
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Blood, 15 July 2003, Vol. 102, No. 2, pp. 549-557
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease
Lee A. O'Brien,
Paula D. James,
Maha Othman,
Ergul Berber,
Cherie Cameron,
Colleen R. P. Notley,
Carol A. Hegadorn,
Jeffrey J. Sutherland,
Christine Hough,
Georges E. Rivard,
Denise O'Shaunessey, and
David Lillicrap, the Association of Hemophilia Clinic Directors of Canada
From the Departments of Pathology and Chemistry, Queen's University, Kingston, ON; the Department of Hematology, Hopital Sainte-Justine, Montreal, PQ, Canada; and the Department of Haematology, University of Southampton, United Kingdom.
To date, no dominant mutation has been identified in a significant proportion of patients with type 1 von Willebrand disease (VWD). In this study, we examined 70 families as part of the Canadian Type 1 VWD Study. The entire VWF gene was sequenced for 1 index case, revealing 2 sequence variations: intron 30 (5312—19A>C) and exon 28 at Tyr1584Cys (4751A>G). The Tyr1584Cys variation was identified in 14.3% (10 of 70) of the families and was in phase with the 5312—19A>C variation in 7 (10.0%) families. Both variants were observed in 2 of 10 UK families with type 1 VWD, but neither variant was found in 200 and 100 healthy, unrelated persons, respectively. Mean von Willebrand factor antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and factor VIII coagulant activity (FVIII:C) for the index cases in these families are 0.4 U/mL, 0.36 U/mL, and 0.54 U/mL, respectively, and VWF multimer patterns show no qualitative abnormalities. Aberrant VWF splicing was not observed in these patients, and both alleles of the VWF gene are expressed as RNA. Molecular dynamic simulation was performed on a homology model of the VWF-A2 domain containing the Tyr1584Cys mutation. This showed that no significant structural changes occur as a result of the substitution but that a new solvent-exposed reactive thiol group is apparent. Expression studies revealed that the Tyr1584Cys mutation results in increased intracellular retention of the VWF protein. We demonstrate that all the families with the Tyr1584Cys mutation share a common, evolved VWF haplotype, suggesting that this mutation is ancient. This is the first report of a mutation that segregates in a significant proportion of patients with type 1 VWD.
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