Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models
| Autor: | Andrea Bryant, Sandra L. Haberichter, Mia Golder, Kate Sponagle, Cynthia M. Pruss, Kimberly Laverty, Erin Burnett, Colleen Notley, Carol Hegadorn, David Lillicrap, Aly S. Dhala |
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| Rok vydání: | 2011 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities medicine.medical_specialty Immunology ADAMTS13 Protein Biochemistry Thrombosis and Hemostasis Cell Line law.invention Mice Von Willebrand factor Antigen In vivo law hemic and lymphatic diseases Internal medicine von Willebrand Factor medicine Animals Humans Mice Knockout biology Metalloendopeptidases Thrombosis Cell Biology Hematology Phenotype Recombinant Proteins ADAMTS13 In vitro ADAM Proteins Disease Models Animal von Willebrand Diseases Endocrinology Mutation Knockout mouse cardiovascular system biology.protein Recombinant DNA Protein Multimerization circulatory and respiratory physiology |
| Zdroj: | Blood. 117:4358-4366 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Type 1 VWD is the mild to moderate reduction of VWF levels. This study examined the mechanisms underlying 2 common type 1 VWD mutations, the severe R1205H and more moderate Y1584C. In vitro biosynthesis was reduced for both mutations in human and mouse VWF, with the effect being more severe in R1205H. VWF knockout mice received hydrodynamic injections of mouse Vwf cDNA. Lower VWF antigen levels were demonstrated in both homozygous and heterozygous forms for both type 1 mutations from days 14-42. Recombinant protein infusions and hydrodynamic-expressed VWF propeptide to antigen ratios demonstrate that R1205H mouse VWF has an increased clearance rate, while Y1584C is normal. Recombinant ADAMTS13 digestions of Y1584C demonstrated enhanced cleavage of both human and mouse VWF115 substrates. Hydrodynamic-expressed VWF shows a loss of high molecular weight multimers for Y1584C compared with wild-type and R1205H. At normal physiologic levels of VWF, Y1584C showed reduced thrombus formation in a ferric chloride injury model while R1205H demonstrated similar thrombogenic activity to wild-type VWF. This study has elucidated several novel mechanisms for these mutations and highlights that the type 1 VWD phenotype can be recapitulated in the VWF knockout hydrodynamic injection model. |
| Databáze: | OpenAIRE |
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