Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin αβ Activation
| Autor: | Berrou, Eliane, Adam, Frédéric, Lebret, Marilyne, Planche, Virginie, Fergelot, Patricia, Issertial, Odile, Coupry, Isabelle, Bordet, Jean-Claude, Nurden, Paquita, Bonneau, Dominique, Colin, Estelle, Goizet, Cyril, Rosa, Jean-Philippe, Bryckaert, Marijke |
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| Přispěvatelé: | Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Talin
Adult Blood Platelets Male Heredity Platelet Function Tests Filamins Telomere-Binding Proteins DNA Mutational Analysis Intestinal Pseudo-Obstruction Integrin alpha2 Integrin beta3 Platelet Glycoprotein GPIIb-IIIa Complex von Willebrand factor Transfection Platelet Activation Cell Line Phenotype Periventricular Nodular Heterotopia Mutation Humans Genetic Predisposition to Disease [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Signal Transduction Protein Binding |
| Zdroj: | Arterioscler Thromb Vasc Biol Arterioscler Thromb Vasc Biol, 2017, 37 (6), pp.1087-1097. ⟨10.1161/ATVBAHA.117.309337⟩ |
| ISSN: | 1524-4636 |
| DOI: | 10.1161/ATVBAHA.117.309337⟩ |
| Popis: | International audience; OBJECTIVE: Dominant mutations of the X-linked filamin A () gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia.APPROACH AND RESULTS: We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: ). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most importantly, patient platelets stimulated with ADP exhibited a marked increase in αβ integrin activation and a parallel increase in talin recruitment to β, contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of αβ activation. Overexpression of mutant FLNa in the HEL megakaryocytic cell line correlated with an increase (compared with wild-type FLNa) in PMA-induced fibrinogen binding to and in talin and kindlin-3 recruitment by αβ.CONCLUSIONS: Altogether, our results are consistent with a less binding of mutant FLNa to β and the facilitated recruitment of talin by β on platelet stimulation, explaining the increased αβ activation and the ensuing gain-of-platelet functions. |
| Databáze: | OpenAIRE |
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