TY - JOUR T1 - Abnormal cytoplasmic extensions associated with active αIIbβ3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome. JF - Blood Coagul Fibrinolysis Y1 - 2015 A1 - Hauschner, Hagit A1 - Mor-Cohen, Ronit A1 - Messineo, Stefania A1 - Mansour, Wissam A1 - Seligsohn, Uri A1 - Savoia, Anna A1 - Rosenberg, Nurit KW - Animals KW - Cell Line KW - Cricetinae KW - Cytoskeleton KW - DNA, Complementary KW - Fibrinogen KW - Genetic Vectors KW - Humans KW - Integrin alpha2 KW - Integrin beta3 KW - Megakaryocytes KW - Mesocricetus KW - Microtubules KW - Mutation, Missense KW - Platelet Glycoprotein GPIIb-IIIa Complex KW - Protein Conformation KW - Protein Interaction Mapping KW - Protein Structure, Tertiary KW - Recombinant Fusion Proteins KW - Sequence Deletion KW - Thrombasthenia KW - Tubulin KW - von Willebrand Factor AB -

Mutations in the ITGA2B or ITGB3 genes that encode for the αIIbβ3 platelet integrin usually cause Glanzmann thrombasthenia, a severe autosomal recessive bleeding disorder characterized by absence of platelet aggregation, but normal platelet number and size. Several rare mutations cause a Glanzmann-like syndrome which manifests macrothrombocytopenia and usually displays autosomal dominant inheritance. The exact mechanism causing Glanzmann-like syndrome is unknown. One typical example of Glanzmann-like mutations causes deletion of 40 amino acids (p.647-686) in the β3 β-tail domain (βTD_del) that was found in the heterozygous state in Italian and Japanese families. A second example is a missense mutation, C560R, located in the epidermal growth factor-like domain, found in the homozygous state in a French patient. Both mutations cause constitutive activation of αIIbβ3, but differ in their surface expression. In the current study, we generated cultured cells expressing β3-βTD_del or β3-C560R mutations along with wild-type αIIb, and examined the cells' ability to create tubulin-dependent protrusions compared to cells expressing wild-type αIIbβ3. Unlike cells expressing wild-type αIIbβ3, cells harboring each of the mutations exhibited abnormal cytoplasmic extensions on immobilized fibrinogen or Von Willebrand factor, which resembled extensions formed in megakaryocyte leading to proplatelets. Moreover, we showed that formation of abnormal extensions occurred also in wild-type αIIbβ3 cells when activated by activating antibody. These results suggest that the active conformation of αIIbβ3 can induce cytoskeletal rearrangements that lead to impaired proplatelet formation.

VL - 26 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25806962?dopt=Abstract ER - TY - JOUR T1 - Spectrum of the mutations in Bernard-Soulier syndrome. JF - Hum Mutat Y1 - 2014 A1 - Savoia, Anna A1 - Kunishima, Shinji A1 - De Rocco, Daniela A1 - Zieger, Barbara A1 - Rand, Margaret L A1 - Pujol-Moix, Núria A1 - Caliskan, Umran A1 - Tokgoz, Huseyin A1 - Pecci, Alessandro A1 - Noris, Patrizia A1 - Srivastava, Alok A1 - Ward, Christopher A1 - Morel-Kopp, Marie-Christine A1 - Alessi, Marie-Christine A1 - Bellucci, Sylvia A1 - Beurrier, Philippe A1 - de Maistre, Emmanuel A1 - Favier, Rémi A1 - Hézard, Nathalie A1 - Hurtaud-Roux, Marie-Françoise A1 - Latger-Cannard, Véronique A1 - Lavenu-Bombled, Cécile A1 - Proulle, Valérie A1 - Meunier, Sandrine A1 - Négrier, Claude A1 - Nurden, Alan A1 - Randrianaivo, Hanitra A1 - Fabris, Fabrizio A1 - Platokouki, Helen A1 - Rosenberg, Nurit A1 - HadjKacem, Basma A1 - Heller, Paula G A1 - Karimi, Mehran A1 - Balduini, Carlo L A1 - Pastore, Annalisa A1 - Lanza, Francois KW - Alleles KW - Bernard-Soulier Syndrome KW - Databases, Nucleic Acid KW - Founder Effect KW - Genetic Variation KW - Humans KW - Mutation KW - Platelet Glycoprotein GPIb-IX Complex KW - Polymorphism, Single Nucleotide KW - von Willebrand Diseases KW - Web Browser AB -

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

VL - 35 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24934643?dopt=Abstract ER -