Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. Blood 2015 Jul 09;126(2):262-9
Date
05/29/2015Pubmed ID
26019279Pubmed Central ID
PMC4497966DOI
10.1182/blood-2014-11-613935Scopus ID
2-s2.0-84937953557 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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.
Author List
Chen J, Hinckley JD, Haberichter S, Jacobi P, Montgomery R, Flood VH, Wong R, Interlandi G, Chung DW, López JA, Di Paola JAuthors
Veronica H. Flood MD Interim Chief, Professor in the Pediatrics department at Medical College of WisconsinRobert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Crystallography, X-RayFamily
Female
HEK293 Cells
Humans
Male
Molecular Docking Simulation
Mutant Proteins
Mutation, Missense
Pedigree
Phenotype
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
von Willebrand Diseases
von Willebrand Factor
