title: A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder.
abstract: BACKGROUND
  The physiological relevance of the collagen glycoprotein VI (GPVI) receptor was known prior to its recognition as a platelet membrane receptor as several patients lacking GPVI as a consequence of autoantibody inhibition presented with a mild bleeding diathesis. Remarkably, patients with a proven GPVI gene mutation have not yet been identified.
  
  
  RESULTS
  In the present study, we describe a patient with a lifelong history of bleeding problems, structurally normal platelets but a functional platelet defect. Platelet aggregations are normal except for an absent response to Horm collagen, convulxin and the collagen-related peptide (CRP). ATP dense granule secretion is normal with ADP but absent with Horm collagen. Thrombus formation on a collagen surface in flowing blood is reduced but more single platelets are attached. Remarkably, the platelet function analyzer-100 shows a shortened collagen/ADP closure time. Flow cytometry demonstrates an absent expression of GPVI whereas immunoblot analysis shows strongly reduced levels of GPVI. The patient is compound heterozygous for an out-of-frame 16-bp deletion and a missense mutation S175N in a highly conserved residue of the 2nd Ig-like GPVI domain. The parents without clinical bleeding problems are heterozygous carriers. The mother carries the S175N mutation and presents with a mild functional platelet defect. In vitro studies show a reduced membrane expression and convulxin binding with the mutated S175N compared with the wild-type (WT) GPVI receptor.
  
  
  CONCLUSIONS
  This study presents the first patient with a proven genetic GPVI defect.
authors: Department of Haematology, Haemostasis and Thrombosis Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors: C
authors: C
authors: Hermans
authors: C
authors: C
authors: Wittevrongel
authors: C
authors: C
authors: Thys
authors: P A
authors: PA
authors: Smethurst
authors: C
authors: C
authors: Van Geet
authors: K
authors: K
authors: Freson
mesh_terms: D000328:Adult; D001778:Blood Coagulation Disorders / Q000235:genetics*; D003435:Crotalid Venoms / Q000378:metabolism; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D009154:Mutation; D010974:Platelet Aggregation / Q000235:genetics; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D011485:Protein Binding; D017455:Receptors, IgE / Q000235:genetics
chemical_list: D003435:Crotalid Venoms; D037181:Lectins, C-Type; D010980:Platelet Membrane Glycoproteins; D017455:Receptors, IgE; C098341:platelet membrane glycoprotein VI; C028890:convulxin