title: The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain.
abstract: Type IIB von Willebrand Disease (vWD) is characterized by the selective loss of large von Willebrand Factor (vWF) multimers from plasma, presumably due to their increased reactivity with platelets and subsequent clearance from the circulation. Using the PCR, one of a panel of four potential missense mutations was identified in each of the 14 patients studied from 11 unrelated families. None of these substitutions was encountered in a large panel of normal DNAs. These changes all represent C----T transitions at CpG dinucleotides, proposed "hot spots" for mutation in the human genome. The four resulting amino acid substitutions, Arg543----Trp, Arg545----Cys, Val553----Met, and Arg578----Gln, are all clustered within the GpIb binding domain of vWF. Disruption of this latter functional domain may explain the pathogenesis of Type IIB vWD. By sequence polymorphism analysis, the Arg543----Trp substitution was shown to have occurred as at least two independent mutational events. This latter observation, along with the identification of mutations in all 14 patients studied and their localization to the GpIb binding domain, all strongly suggest that these substitutions represent the authentic defects responsible for Type IIB vWD. This panel of mutations may provide a useful diagnostic tool for the majority of patients with Type IIB vWD.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0650.
authors.forename: K A
authors.initials: KA
authors.lastname: Cooney
authors.forename: W C
authors.initials: WC
authors.lastname: Nichols
authors.forename: M E
authors.initials: ME
authors.lastname: Bruck
authors.forename: W F
authors.initials: WF
authors.lastname: Bahou
authors.forename: A D
authors.initials: AD
authors.lastname: Shapiro
authors.forename: E J
authors.initials: EJ
authors.lastname: Bowie
authors.forename: H R
authors.initials: HR
authors.lastname: Gralnick
authors.forename: D
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011485:Protein Binding; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D009841:Oligonucleotides; D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor