Journal
BLOOD
Volume 121, Issue 11, Pages 2135-2143Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-09-456038
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Funding
- Institut National de la Sante et de la Recherche Medicale
- Laboratoires Francais de Fractionnement et des Biotechnologies
- Agence Nationale de la Recherche [ANR-08-EBIO-026-01, ANR-08-CEXC-018-01]
- Fondation pour la Recherche Medicale [FRM-SPF2010220866]
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Two unrelated families were recruited in the French Reference Center for von Willebrand Disease with moderate bleeding symptoms associated with low von Willebrand factor (VWF) antigen levels, decreased collagen binding assay, and no or partial response to desmopressin. Genetic analysis showed the presence of heterozygous mutations in the A3 domain away from the collagen-binding surface: 1 never reported previously (p.L1696R) and another (p.P1824H) described in a Spanish family. The mutations were reproduced by site-directed mutagenesis and mutant VWF was expressed in different expression systems, COS-7 cells, baby hamster kidney cells, and in VWF-deficient mice through hydrodynamic injection. p.L1696R and p.P1824H were associated with very low expression levels both in vitro and in vivo, with intracellular retention for p.P1824H. Both homozygous mutants displayed decreased binding to collagen types I and III but also decreased binding to platelet glycoproteins Ib and IIbIIIa. Co-transfections with wild-type VWF partially corrected these defects, except that collagen binding remained abnormal. The in vivo thrombosis response was severely reduced for both heterozygous mutants. In conclusion, we report 2 VWF A3 domain mutations that induce a combined qualitative and quantitative defect.
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