Novel cysteine substitution p.(Cys1084Tyr) causes variable expressivity of qualitative and quantitative VWF defects

Autor:	Orla Rawley, Laura L. Swystun, Christine Brown, Kate Nesbitt, Margaret Rand, Taneya Hossain, Robert Klaassen, Paula D. James, Manuel D. Carcao, David Lillicrap
Rok vydání:	2022
Předmět:	Mice von Willebrand Diseases congenital hereditary and neonatal diseases and abnormalities hemic and lymphatic diseases von Willebrand Factor Animals Cysteine Disulfides von Willebrand Disease Type 2 Hematology circulatory and respiratory physiology
Zdroj:	Blood Advances. 6:2908-2919
ISSN:	2473-9537 2473-9529
DOI:	10.1182/bloodadvances.2021005928
Popis:	von Willebrand factor (VWF) is an extremely cysteine-rich multimeric protein that is essential for maintaining normal hemostasis. The cysteine residues of VWF monomers form intra- and intermolecular disulfide bonds that regulate its structural conformation, multimer distribution, and ultimately its hemostatic activity. In this study, we investigated and characterized the molecular and pathogenic mechanisms through which a novel cysteine variant p.(Cys1084Tyr) causes an unusual, mixed phenotype form of von Willebrand disease (VWD). Phenotypic data including bleeding scores, laboratory values, VWF multimer distribution, and desmopressin response kinetics were investigated in 5 members (2 parents and 3 daughters) of a consanguineous family. VWF synthesis and secretion were also assessed in a heterologous expression system and in a transient transgenic mouse model. Heterozygosity for p.(Cys1084Tyr) was associated with variable expressivity of qualitative VWF defects. Heterozygous individuals had reduced VWF:GPIbM (
Databáze:	OpenAIRE
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