A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B "Malmo/New York" von Willebrand disease

作者：Lavenu Bombled Cecile; Guitton Corinne; Dupuis Arnaud; Baas Marie Jeanne; Desconclois Celine; Dreyfus Marie; Li Renhao; Caron Claudine; Gachet Christian; Fressinaud Edith; Lanza Francois^*

来源：Thrombosis and Haemostasis, 2016, 116(6): 1070-1078.

DOI：10.1160/TH16-06-0438

• Haemostasis
• haemorrhagic disorders
• platelet
• von Willebrand factor
• von Willebrand disease

Interaction between von Willebrand factor (VWF) and platelet GPIb alpha 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 GPIba 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 Malmo/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 GPIb alpha to Ile. This new mutation is located in the beta-switch domain where five other gain-of-function mutations have been reported in PT-VWD. Expression of GPIb alpha 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.

• 出版日期2016-12