title: Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome.
abstract: Filaminopathies A caused by mutations in the X-linked FLNA gene are responsible for a wide spectrum of rare diseases including 2 main phenotypes, the X-linked dominant form of periventricular nodular heterotopia (FLNA-PVNH) and the otopalatodigital syndrome spectrum of disorders. In platelets, filamin A (FLNa) tethers the principal receptors ensuring the platelet-vessel wall interaction, glycoprotein Ibα and integrin αIIbβ3, to the underlying cytoskeleton. Hemorrhage, coagulopathy, and thrombocytopenia are mentioned in several reports on patients with FLNA-PVNH. Abnormal platelet morphology in 2 patients with FLNA-PVNH prompted us to examine a third patient with similar platelet morphology previously diagnosed with immunologic thrombocytopenic purpura. Her enlarged platelets showed signs of FLNa degradation in Western blotting, and a heterozygous missense mutation in FLNA was detected. An irregular distribution of FLNa within the total platelet population was shown by confocal microscopy for all 3 patients. In vitro megakaryocyte cultures showed an abnormal differentiation, including an irregular distribution of FLNa with a frayed aspect, the presence of enlarged α-granules, and an abnormal fragmentation of the cytoplasm. Mutations in FLNA may represent an unrecognized cause of macrothrombocytopenia with an altered platelet production and a modified platelet-vessel wall interaction.
authors.affiliation: Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France. paquita.nurden@cnrshl.u-bordeaux2.fr
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupry
authors.forename: Marijke
authors.initials: M
authors.lastname: Bryckaert
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Youlyouz-Marfak
authors.forename: Guilhem
authors.initials: G
authors.lastname: Solé
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Pons
authors.forename: Eliane
authors.initials: E
authors.lastname: Berrou
authors.forename: Frédéric
authors.initials: F
authors.lastname: Adam
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kauskot
authors.forename: Jean-Marie Daniel
authors.initials: JM
authors.lastname: Lamazière
authors.forename: Philippe
authors.initials: P
authors.lastname: Rameau
authors.forename: Patricia
authors.initials: P
authors.lastname: Fergelot
authors.forename: Caroline
authors.initials: C
authors.lastname: Rooryck
authors.forename: Dorothée
authors.initials: D
authors.lastname: Cailley
authors.forename: Benoît
authors.initials: B
authors.lastname: Arveiler
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Alan
authors.initials: A
authors.lastname: Nurden
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000235:genetics*; D005260:Female; D064448:Filamins; D020022:Genetic Predisposition to Disease; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D010976:Platelet Count; D013577:Syndrome; D013921:Thrombocytopenia / Q000097:blood / Q000145:classification* / Q000175:diagnosis / Q000235:genetics*
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins