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

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

Distribution of bone morphogenetic protein and bone morphogenetic protein receptor transcripts in the rodent nervous system and up-regulation of bone morphogenetic protein receptor type II in hippocampal dentate gyrus in a rat model of global cerebral ischemia.

Bone morphogenetic proteins belong to the transforming growth factor-beta superfamily and act through serine/threonine kinase type I and type II receptors such as bone morphogenetic protein receptor type I and type II. In order to further understand the roles that these factors exert in the nervous system, we have examined the expression pattern of seven bone morphogenetic proteins and bone morphogenetic protein receptor type I and II transcripts in the brain and spinal cord of rodent. Whereas bone morphogenetic protein receptor type I expression was low in rat brain, in situ hybridization studies performed with specific digoxigenin-labelled riboprobes revealed the presence of bone morphogenetic protein receptor type II-positive cells throughout the brain, with a notable localization in dopaminergic cells of the substantia nigra. Bone morphogenetic protein receptor type II transcripts were also expressed by large motoneuron-like cells located in the ventral horn of the spinal cord and by sensory neurons of dorsal root ganglia. In addition, we observed a significant up-regulation of bone morphogenetic protein receptor type II in the granule cells of the dentate gyrus 48 h after transient global cerebral ischemia in rat suggesting that modulation of this receptor intervenes during neuronal plasticity or repair that occur upon brain injury. Among the potential ligands for this receptor, bone morphogenetic protein-6 and bone morphogenetic protein-7 were expressed in meninges and the choroid plexus, while bone morphogenetic protein-4-expressing cells were spatially and temporally regulated in myelinated structures during development and in the adult suggesting its expression in oligodendrocytes.These data clearly indicate that besides their roles in bone and embryonic tissues, bone morphogenetic proteins and their receptors may have also important functions in adult neural tissues