Type 2M:Milwaukee-1 von Willebrand disease: an in-frame deletion in the Cys509-Cys695 loop of the von Willebrand factor A1 domain causes deficient binding of von Willebrand factor to platelets. Blood 1996 Oct 01;88(7):2559-68
Date
10/01/1996Pubmed ID
8839848DOI
10.1182/blood.v88.7.2559.bloodjournal8872559Scopus ID
2-s2.0-0029796142 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
This report examines the genetic basis of a variant form of moderately severe von Willebrand disease (vWD) characterized by low plasma von Willebrand factor antigen (vWF:Ag) levels and normal multimerization, typical of type 1 vWD, but disproportionately-low agonist-mediated platelet-binding activity. We identified an in-frame deletion in vWF exon 28 in three generations of affected family members, who are heterozygous for this mutation. The deletion of nucleotides 4,173-4,205 results in the loss of amino acids Arg629-Gln639 in the Cys509-Cys695 loop of the A1 domain in mature vWF. The secreted mutant vWF showed a normal multimeric profile but did not bind to platelets in the presence of optimal concentrations of either ristocetin or botrocetin. The mutant vWF also failed to interact with heparin, and with vWF monoclonal antibody AvW3, which blocks the binding of vWF to GPlb. In addition, mutant vWF showed reduced secretion from transfected cells concomitant with increased intracellular levels. These results confirm that the deletion is the genetic defect responsible for the reduced interaction of vWF with platelets. We have designated this new variant type 2M:Milwaukee-1 vWD. Our analysis suggests that the potential frequency of this phenotype in individuals diagnosed with type 1 vWD is about 0.5%.
Author List
Mancuso DJ, Kroner PA, Christopherson PA, Vokac EA, Gill JC, Montgomery RRAuthor
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAmino Acid Sequence
Base Sequence
Blood Platelets
Crotalid Venoms
DNA Mutational Analysis
Female
Heparin
Heterozygote
Humans
Male
Molecular Sequence Data
Pedigree
Phenotype
Platelet Membrane Glycoproteins
Protein Binding
Protein Structure, Tertiary
Receptors, Cell Surface
Recombinant Fusion Proteins
Ristocetin
Sequence Alignment
Sequence Deletion
Sequence Homology
von Willebrand Diseases
von Willebrand Factor
