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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-12-3693.
Submitted December 9, 2002
Accepted March 5, 2003
A 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 Notley, Carol A Hegadorn, Jeffery J Sutherland, Christine Hough, Georges E Rivard, Denise O'Shaunessey, the Association of Hemophilia Clinic Directors of Canada, and David Lillicrap*
Department of Pathology, Queen's University, Kingston, ON, Canada
Department of Haematology, University of Southampton, Southampton, United Kingdom
Department of Chemistry, Queen's University, Kingston, ON, Canada
Department of Hematology/Oncology, Hopital Sainte-Justine, Montreal, PQ, Canada
* Corresponding author; email: lillicrap{at}cliff.path.queensu.ca.
To date, no dominant mutation has been identified in a significant proportion of type 1 VWD patients. In this study, we examined 70 families collected as part of the Canadian Type 1 VWD Study. The entire VWF gene was sequenced for one index case, revealing two sequence variations; intron 30 (5312-18A C) and exon 28 at Y1584C (4751AG). The Y1584C variation was identified in 14.3% (10/70) of the families and was in phase with the 5312-18AC variation in 7 families (10.0%). Both variants were observed in 2/10 UK type 1 VWD families but neither variant was found in 200 and 100 normal, unrelated individuals, respectively. The mean VWF:Ag, VWF:RCo and 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 the 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. A molecular dynamic simulation was performed on a homology model of the VWF-A2 domain, containing the Y1584C mutation. This showed that no significant structural changes occur as a result of the substitution but a new, solvent exposed reactive thiol group is apparent. Expression studies revealed that the Y1584C mutation results in increased intracellular retention of the VWF protein. We demonstrate that all of the families with the Y1584C mutation share a common, evolved VWF haplotype suggesting that this mutation is ancient. This is the first report of a mutation that segregates with a significant proportion of type 1 VWD patients.
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