title: Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding.
abstract: A novel mutation, R1308L (3923G > T) was present in the heterozygous state in five members of a family with type 2B von Willebrand disease (VWD) characterized by a full set of von Willebrand factor (VWF) multimers in plasma and by the absence of thrombocytopenia before and after desmopressin (DDAVP). The defect (R1308L) was located at the same amino acid position of one of the most common mutations associated with type 2B VWD (R1308C), which is characterized by the loss of high molecular weight VWF multimers (HMWM) in plasma and the occurrence of thrombocytopenia. To understand the mechanisms of this defect, the novel (R1308L) and 'common' (R1308C) mutations were expressed in COS-7 cells, either alone or, to mimic the patients' heterozygous state, together with wild-type VWF. R1308L recombinant VWF (rVWF) had a higher affinity for the platelet glycoprotein Ibalpha (GPIbalpha) receptor than wild-type rVWF, R1308C rVWF showing an even higher affinity. A novel finding was that both mutant rVWFs showed a similarly reduced binding to collagen type I and type III in comparison with wild-type rVWF. The latter finding suggests a more important role than recognized so far for the VWF A1 domain in VWF binding to collagen, which may contribute to the in vivo hemostatic defect associated with type 2B VWD.
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center, Department of Internal Medicine and Dermatology IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation and University of Milan, Milan, Italy. luciano.baronciani@unimi.it
authors.forename: L
authors.initials: L
authors.lastname: Baronciani
authors.forename: A B
authors.initials: AB
authors.lastname: Federici
authors.forename: M
authors.initials: M
authors.lastname: Beretta
authors.forename: G
authors.initials: G
authors.lastname: Cozzi
authors.forename: M T
authors.initials: MT
authors.lastname: Canciani
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003094:Collagen / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism; D020125:Mutation, Missense; D019038:Platelet Glycoprotein GPIb-IX Complex; D011485:Protein Binding / Q000235:genetics; D014161:Transduction, Genetic; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor; D003094:Collagen