Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease

Junmei Chen, Jesse D. Hinckley, Sandra Haberichter, Paula Jacobi, Robert Montgomery, Veronica H. Flood, Randall Wong, Gianluca Interlandi, Dominic W. Chung, José A. López, Jorge Di Paola

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

VonWillebrand 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 manifestsasanautosomal-dominant trait,withclinicalandbiochemicalphenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, andmultimer pattern. Sequencing of allVWFcoding 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 thewildtype 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 containeddifferentpercentagesofmutantmonomersindifferent individuals.Thus, theobservedvariability inVWDphenotypescouldinpart be determined by the extent ofmutantmonomer incorporation in the final multimer structure of plasma VWF.

Original languageEnglish
Pages (from-to)262-269
Number of pages8
JournalBlood
Volume126
Issue number2
DOIs
StatePublished - Jul 9 2015

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