Summary.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by lack or dysfunction of αIIbβ3 in platelets. GT is relatively frequent in highly inbred populations. We previously identified a 13‐bp deletion in the αIIb gene that causes in‐frame deletion of six amino acids in three Palestinian GT patients. In this study, we determined the molecular basis of GT in all known Palestinian patients, examined whether Jordanian patients harbor the same mutations, analyzed whether there is a founder effect for the 13‐bp deletion, and determined the mechanism by which the 13‐bp deletion abolishes αIIbβ3 surface expression. Of 11 unrelated Palestinian patients, eight were homozygous for the 13‐bp deletion that displayed common ancestry by haplotype analysis, and was estimated to have occurred 300–600 years ago. Expression studies in baby hamster kidney cells showed that substitution of Cys107 or Trp110 located within the deletion caused defective αIIbβ3 maturation. Substitution of Trp110, but not of Cys107, prevented fibrinogen binding. The other Palestinian patients harbored three novel mutations: G2374 deletion in αIIb gene, TT1616‐7 deletion in β3 gene, and IVS14: −3C → G in β3 gene. The latter mutation caused cryptic splicing predicting an extended cytoplasmic tail of β3 and was expressed as dysfunctional αIIbβ3. None of 15 unrelated Jordanian patients carried any of the described mutations.
Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small-platelet thrombocytopenia. J Thromb Haemost 2015; 13, 1285-92.Summary. Background: The FYB gene encodes adhesion and degranulation-promoting adaptor protein (ADAP), a hematopoietic-specific protein involved in platelet activation, cell motility and proliferation, and integrin-mediated cell adhesion. No ADAP-related diseases have been described in humans, but ADAP-deficient mice have mild thrombocytopenia and increased rebleeding from tail wounds. Patients and methods: We studied a previously reported family of five children from two consanguineous sibships of Arab Christian descent affected with a novel autosomal recessive bleeding disorder with small-platelet thrombocytopenia. Homozygosity mapping and exome sequencing were used to identify the genetic lesion causing the disease phenotype on chromosome 5. Bone-marrow morphology and platelet function were analyzed. Platelets were characterized by scanning electron microscopy. Results: We identified a homozygous deleterious nonsense mutation, c.393G>A, in FYB. A reduced percentage of mature megakaryocytes was found in the bone marrow. Patients' platelets showed increased basal expression of P-selectin and PAC-1, and reduced increments of activation markers after stimulation with ADP, as detected by flow cytometry; they also showed reduced pseudopodium formation and the presence of trapped platelets between the fibrin fibers after thrombin addition, as observed on scanning electron microscopy. Conclusions: This is the first report of a disease caused by an FYB defect in humans, manifested by remarkable small-platelet thrombocytopenia and a significant bleeding tendency. The described phenotype shows ADAP to be important for normal platelet production, morphologic changes, and function. It is suggested that mutation analysis of this gene be included in the diagnosis of inherited thrombocytopenia.
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