FLNA p.V528M substitution is neither associated with bilateral periventricular nodular heterotopia nor with macrothrombocytopenia

Abstract

Filamin A is encoded by the FLNA gene on chromosome Xq28 and functions in cross-linking actin filaments into orthogonal networks in the cortical cytoplasm. FLNA p.V528M was initially detected in a female autopsy case of X-linked bilateral periventricular nodular heterotopia (BPNH), a neuronal migration disorder characterized by subependymal nodules of gray matter. During our mutation analysis of FLNA in a boy with apparent X-linked thrombocytopenia, we detected the p.V528M variant. The patient, mother and sister, who were heterozygous for the substitution, did not have BPNH. We observed an allele frequency of 4.8% in healthy control Japanese, but did not observe the variant in Caucasian subjects. Hemizygous controls had a normal platelet count and size. We suggest that p.V528M is neither associated with BPNH nor with thrombocytopenia and giant platelets, and represents a functional polymorphism.

FlnA-null megakaryocytes prematurely release large and fragile platelets that circulate poorly

“…10,26,27 Large platelets and low platelet counts have been described in some, but not all, periventricular heterotopia patients with FLNA mutations. [28][29][30] It is probable that only mutations that cause loss of the FlnA-GPIb␣ linkage lead to morphologic platelet defects. However, a significant platelet phenotype may be hindered in females with only one mutant allele, the vast majority of periventricular heterotopia patients with FLNA mutations, as FLNA is X-linked and platelets expressing full-length FlnA are expected to have a selective advantage in vivo.…”

Platelet size: finding the right balance

“…6,7 In platelets, FlnA anchors the von Willebrand factor receptor GPIb-IX-V complex and ␤1 and ␤3 integrins to the underlying actin cytoskeleton. Mice specifically lacking FlnA in the megakaryocyte lineage, such as FLNA loxP GATA1-Cre and FLNA loxP PF4-Cre mice, have a severe thrombocytopenia, enlarged platelets, and increased tail bleeding time, 3,4 similar to GPIb␣-null mice.…”

“…memory CAR ϩ T cells contributing to antitumor effects; (3) evidence of replication senescence among manufactured T cells; (4) the role for administration of exogenous cytokines; (5) the role of B cells to serve as an in vivo cellular substrate to enhance T-cell persistence; (6) whether T cells can be administered in states of minimal disease; and (7) whether to ablate CAR ϩ T cells to restore normal B-cell number and function. Trials are now under way in many countries infusing CAR ϩ T cells targeting a variety of tumor-associated antigens in an attempt to address all these issues.…”

New aspects of Filamin A versatility

“…4 These risks are most marked in women with antithrombin, protein C, or protein S deficiency, 5 while thrombotic risks are much more modest in women with the common mild thrombophilias of heterozygosity for factor V Leiden or the prothrombin gene mutation. 6 In recent years, laboratory testing for thrombophilia has been performed on increasing numbers of patients, including…”

“…Recently, the p.V528M variant was found in a patient with suspected X-linked macrothrombocytopenia and classified as functional polymorphism because no associations were found with neither BPNH nor macrothrombocytopenia. 6 Interestingly, in a previous paper, the Falet group has shown that Filamin A loxP/y GATA1-Cre mice, which lack filamin A in platelets, present macrothrombocytopenia with decreased expression and functional impairment of GPIb␣. 7 In this issue of Blood, Jurak Begonja et al propose a multifaceted mechanism that leads to macrothrombocytopenia in the absence of filamin A in a PF4-Cre transgenic mouse model.…”