title: Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small-platelet thrombocytopenia.
abstract: 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.
  
  
  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.
authors: Pediatric Hematology Unit and Pediatric Department B, Emek Medical Center, Afula, Israel.|The Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors: C
authors: C
authors: Levin
authors: Pediatric Hematology Unit and Pediatric Department B, Emek Medical Center, Afula, Israel.|The Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors: A
authors: A
authors: Koren
authors: Department of Anatomy, Faculty of Health Sciences, School of Medicine of the University of Pretoria, Gauteng, South Africa.
authors: E
authors: E
authors: Pretorius
authors: Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: N
authors: N
authors: Rosenberg
authors: Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: B
authors: B
authors: Shenkman
authors: Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: H
authors: H
authors: Hauschner
authors: Hematology Laboratory, Emek Medical Center, Afula, Israel.
authors: L
authors: L
authors: Zalman
authors: Genetic Institute, Emek Medical Center, Afula, Israel.
authors: M
authors: M
authors: Khayat
authors: Clalit Health Services, Afula, Israel.
authors: I
authors: I
authors: Salama
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: O
authors: O
authors: Elpeleg
authors: The Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.|Genetic Institute, Emek Medical Center, Afula, Israel.
authors: S
authors: S
authors: Shalev
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D018912:Arabs / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure*; D048429:Cell Size; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D054641:Dual Specificity Phosphatase 2 / Q000097:blood; D059472:Exome; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D006487:Hemostasis / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008855:Microscopy, Electron, Scanning; D019007:P-Selectin / Q000097:blood; D010375:Pedigree; D010641:Phenotype; D010979:Platelet Function Tests; D011237:Predictive Value of Tests; D012307:Risk Factors; D013921:Thrombocytopenia / Q000097:blood / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C106957:FYB1 protein, human; D005819:Genetic Markers; D019007:P-Selectin; C546937:SELP protein, human; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2
keywords: adaptor proteins; blood platelet disorders; humans; inherited blood coagulation disorders; mutation; signal transducing