A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B 'Malmö/New York' von Willebrand disease
| Autor: | Edith Fressinaud, Marie Dreyfus, Corinne Guitton, Claudine Caron, Celine Desconclois, Marie-Jeanne Baas, Arnaud Dupuis, Cécile Lavenu-Bombled, François Lanza, Renhao Li, Christian Gachet |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blood Platelets Male congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty 030204 cardiovascular system & hematology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Von Willebrand factor hemic and lymphatic diseases Internal medicine von Willebrand Factor Von Willebrand disease medicine Platelet-Type von Willebrand Disease Humans Platelet Child Mutation biology Chemistry HEK 293 cells Hematology medicine.disease Phenotype GP1BA von Willebrand Diseases 030104 developmental biology Endocrinology Platelet Glycoprotein GPIb-IX Complex biology.protein Female |
| Zdroj: | Thrombosis and haemostasis. 116(6) |
| ISSN: | 2567-689X |
| Popis: | SummaryInteraction between von Willebrand factor (VWF) and platelet GPIbα is required for primary haemostasis. Lack or loss-of-function in the ligand-receptor pair results in bleeding complications. Paradoxically, gain-of-function mutations in VWF or GPIbα also result in bleeding complications as observed in type 2B von Willebrand disease (VWD) and platelet-type- (PT-) VWD, respectively. A similar phenotype is observed with increased ristocetin-induced platelet agglutination and disappearance of the highest molecular weight multimers of VWF. We evaluated a patient with a bleeding disorder and a biological presentation compatible with type 2B VWD. VWF and platelet functional assays, sequencing of the VWF and GP1BA genes, and expression studies in HEK cells were performed. Sequencing of the VWF gene in the propositus revealed a heterozygous p.Pro1266Leu mutation previously found in type 2B VWD Malmö/New York. These variants are characterised by a mild phenotype and a normal VWF multimer composition suggesting the presence of a second mutation in our propositus. Sequencing of the GP1BA gene revealed a heterozygous c.765G>A substitution changing Met at position 255 of GPIbα to Ile. This new mutation is located in the β-switch domain where five other gain-of-function mutations have been reported in PT-VWD. Expression of GPIbα Ile255 in HEK GPIb-IX cells resulted in enhanced VWF binding compared to wild-type, similar to known PT-VWD mutations (p.Val249, p.Ser249 and p.Val255) indicating that it contributes to the propositus defects. This first report associating PT-with type 2B VWD illustrates the importance of combining biological assays with genetic testing to better understand the clinical phenotype. |
| Databáze: | OpenAIRE |
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