title: Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.
abstract: Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.
authors.affiliation: Bloodworks Research Institute-Puget Sound Seattle, WA;
authors.forename: Junmei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and Human Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO;
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Hinckley
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin and Department of Pediatrics, Milwaukee, WI; Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Sandra
authors.initials: S
authors.lastname: Haberichter
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin and Department of Pediatrics, Milwaukee, WI;
authors.forename: Paula
authors.initials: P
authors.lastname: Jacobi
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin and Department of Pediatrics, Milwaukee, WI;
authors.forename: Robert
authors.initials: R
authors.lastname: Montgomery
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin and Department of Pediatrics, Milwaukee, WI;
authors.forename: Veronica H
authors.initials: VH
authors.lastname: Flood
authors.affiliation: DNA Core, Barbara Davis Diabetes Center, University of Colorado Anschutz Medical Campus, Aurora, CO;
authors.forename: Randall
authors.initials: R
authors.lastname: Wong
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA; and.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Interlandi
authors.affiliation: Bloodworks Research Institute-Puget Sound Seattle, WA;
authors.forename: Dominic W
authors.initials: DW
authors.lastname: Chung
authors.affiliation: Bloodworks Research Institute-Puget Sound Seattle, WA; Departments of Biochemistry and Medicine, University of Washington, Seattle, WA.
authors.forename: José A
authors.initials: JA
authors.lastname: López
authors.affiliation: Department of Pediatrics and Human Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO;
authors.forename: Jorge
authors.initials: J
authors.lastname: Di Paola
mesh_terms: D018360:Crystallography, X-Ray; D005190:Family; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D050505:Mutant Proteins / Q000378:metabolism*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D055503:Protein Multimerization / Q000502:physiology; D017434:Protein Structure, Tertiary; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D014841:von Willebrand Factor