A B3 ASP217VAL SUBSTITUTION IN A PATIENT WITH VARIANT GLANZMANN THROMBATHENIA SEVERELY AFFECTS INTEGRIN AIIBB3 FUNCTIONS
Abstract number: P-T-274
D'Andrea1 G., D'Ambrosio2 R.R.D., Del Vecchio3 L.L.D., Amoriello4 A.A.A., Chinni1 E.E.C., Santacroce1 R.R.S., Sarno1 M.M.S., Bafunno1 V.V.B., Longo5 V.V.L., Vecchione6 G.G.V., Grandone6 E.E.G., Margaglione1 M.M.M.
11Scienze Biomediche, Servizio di Genetica Medica, Universita' Degli Studi di Foggia, Foggia 22I.R.C.C.S. " Casa Sollievo Della Sofferenza", Casa Sollievo Sofferenza, San Giovanni Rotondo(Fg), Italy 33Centro Trasfusionale, Ospedale Cardarelli, Napoli 44Centro Trasfusionale, Ospedale Cardarelli, Napoli 55Scienze Chirurgiche, Universita' Degli Studi di Foggia, Foggia 66I.R.C.C.S., Casa Sollievo Sofferenza, San Giovanni Rotondo(Fg), Italy
How-to-cite D'Andrea G, D'Ambrosio RRD, Del Vecchio LLD, Amoriello AAA, Chinni EEC, Santacroce RRS, Sarno MMS, Bafunno VVB, Longo VVL, Vecchione GGV, Grandone EEG, Margaglione MMM. A B3 ASP217®VAL SUBSTITUTION IN A PATIENT WITH VARIANT GLANZMANN THROMBATHENIA SEVERELY AFFECTS INTEGRIN AIIBB3 FUNCTIONS. J Thromb Haemost 2007; 5 Supplement 2: P-T-274
Abstract
Introduction: Glanzmann Thromboasthenia (GT) is a rare bleeding disorder due to qualitative or quantitative abnormalities of platelets aIIbb3 heterodimers. A dysfunctional defect is far less frequent and is know as "variant" GT. In variant GT, laboratory tests show normal levels of aIIbb3 heterodimer on the platelet surface that are unable to bind ligands as fibrinogen. This connection is regulated by a dynamically conformational change of aIIbb3 and this complex mechanism is not fully understood. For these reasons, genotyping and functional analysis of variant GT is important to elucidate the molecular basis of aIIbb3 receptor functions
Methods: In this report we have analyzed the molecular effects of an A>T substitution leading to an aminoacid change, D217>V, in the b3 integrin gene identified in a patients with variant GT. Since the D217 residue is highly conserved among all seven b integrin subunits and among b3 integrins of different species, we tested the effect on the phenotype of the D217V mutation by co-transfecting the b3 mutant (V217) or wild-type b3 (D217) construct with the wild-type aIIb into eukaryotic CHO cells
Results: Levels of mutant aIIbb3 heterodimers on CHO cell surface were lightly reduced as compared with the wild-type. Functional investigation of aIIbb3 V217 on CHO cell surface, as fibrinogen binding, adhesion and aggregation test showed a substantial reduction in respect to the control sample
Conclusions: Our results confirm "ex vivo" data and suggest that the D217 aminoacid is required for aIIbb3 receptor interactions with fibrinogen.
