title: Heterogeneity of platelet functional alterations in patients with filamin A mutations.
abstract: OBJECTIVE
  We examined platelet functions in 4 unrelated patients with filaminopathy A caused by dominant mutations of the X-linked filamin A (FLNA) gene.
  
  
  RESULTS
  Patients P1, P2, and P4 exhibited periventricular nodular heterotopia, heterozygozity for truncating FLNA mutations, and thrombocytopenia (except P2). P3 exhibited isolated thrombocytopenia and heterozygozity for a p.Glu1803Lys FLNA mutation. Truncated FLNA was undetectable by Western blotting of P1, P2, and P4 platelets, but full-length FLNA was detected at 37%, 82%, and 57% of control, respectively. P3 FLNA (p.Glu1803Lys and full-length) was assessed at 79%. All patients exhibited a platelet subpopulation negative for FLNA. Platelet aggregation, secretion, glycoprotein VI signaling, and thrombus growth on collagen were decreased for P1, P3, and P4, but normal for P2. For the 2 patients analyzed (P1 and P4), spreading was enhanced and, more markedly, in FLNA-negative platelets, suggesting that FLNA negatively regulates cytoskeleton reorganization. Platelet adhesion to von Willebrand factor under flow correlated with platelet full-length FLNA content: markedly reduced for P1 and P4 and unchanged for P2. Interestingly, von Willebrand factor flow adhesion was increased for P3, consistent with a gain-of-function effect enhancing glycoprotein Ib-IX-V/von Willebrand factor interaction. These results are consistent with a positive role for FLNA in platelet adhesion under high shear.
  
  
  CONCLUSIONS
  FLNA mutation heterogeneity correlates with different platelet functional impacts and points to opposite regulatory roles of FLNA in spreading and flow adhesion under shear.
authors.affiliation: INSERM, U770, Le Kremlin Bicêtre, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Berrou
authors.forename: Frédéric
authors.initials: F
authors.lastname: Adam
authors.forename: Marilyne
authors.initials: M
authors.lastname: Lebret
authors.forename: Patricia
authors.initials: P
authors.lastname: Fergelot
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kauskot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupry
authors.forename: Martine
authors.initials: M
authors.lastname: Jandrot-Perrus
authors.forename: Alan
authors.initials: A
authors.lastname: Nurden
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rosa
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Marijke
authors.initials: M
authors.lastname: Bryckaert
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D048430:Cell Shape / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003285:Contractile Proteins / Q000235:genetics*; D003435:Crotalid Venoms / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D064448:Filamins; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D037181:Lectins, C-Type; D008840:Microfilament Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000097:blood* / Q000150:complications / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics*; D010973:Platelet Adhesiveness / Q000235:genetics; D010974:Platelet Aggregation / Q000235:genetics; D010979:Platelet Function Tests; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000235:genetics; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D003285:Contractile Proteins; D003435:Crotalid Venoms; D064448:Filamins; D037181:Lectins, C-Type; D008840:Microfilament Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D014841:von Willebrand Factor; C028890:convulxin; D005340:Fibrinogen; D003094:Collagen