Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin α_IIbβ₃ Activation

Dominant mutations of the X-linked filamin A (FLNA) 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.

We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked FLNA allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: p.Ter2648SerextTer101). 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 α_IIbβ₃ integrin activation and a parallel increase in talin recruitment to β₃, contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of α_IIbβ₃ 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 α_IIbβ₃.

Altogether, our results are consistent with a less binding of mutant FLNa to β₃ and the facilitated recruitment of talin by β₃ on platelet stimulation, explaining the increased α_IIbβ₃ activation and the ensuing gain-of-platelet functions.