Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage
| Autor: | Joan Cox Gill, Sandra L. Haberichter, Paula M. Jacobi, Kenneth D. Friedman, Veronica H. Flood, David Jakab |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Von Willebrand factor type A domain Proteolysis Immunology Mutation Missense ADAMTS13 Protein von Willebrand Disease Type 2 Biology Transfection Biochemistry Thrombosis and Hemostasis Von Willebrand factor Internal medicine hemic and lymphatic diseases von Willebrand Factor medicine Humans Platelet Secretion Family medicine.diagnostic_test ADAMTS Cell Biology Hematology Molecular biology ADAMTS13 ADAM Proteins Protein Transport Endocrinology HEK293 Cells biology.protein Female Protein Multimerization ADAMTS Proteins Protein Processing Post-Translational Signal Transduction |
| Zdroj: | Blood. 119(19) |
| ISSN: | 1528-0020 |
| Popis: | Type 2A VWD is characterized by the absence of large VWF multimers and decreased platelet-binding function. Historically, type 2A variants are subdivided into group 1, which have impaired assembly and secretion of VWF multimers, or group 2, which have normal secretion of VWF multimers and increased ADAMTS13 proteolysis. Type 2A VWD patients recruited through the T. S. Zimmerman Program for the Molecular and Clinical Biology of VWD study were characterized phenotypically and potential mutations identified in the VWF D2, D3, A1, and A2 domains. We examined type 2A variants and their interaction with WT-VWF through expression studies. We assessed secretion/intracellular retention, multimerization, regulated storage, and ADAMTS13 proteolysis. Whereas some variants fit into the traditional group 1 or 2 categories, others did not fall clearly into either category. We determined that loss of Weibel-Palade body formation is associated with markedly reduced secretion. Mutations involving cysteines were likely to cause abnormalities in multimer structure but not necessarily secretion. When coexpressed with wild-type VWF, type 2A variants negatively affected one or more mechanisms important for normal VWF processing. Type 2A VWD appears to result from a complex intersection of mechanisms that include: (1) intracellular retention or degradation of VWF, (2) defective multimerization, (3) loss of regulated storage, and (4) increased proteolysis by ADAMTS13. |
| Databáze: | OpenAIRE |
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