An adenine insertion in exon 6 of human GP 6 generates a truncated protein associated with a bleeding disorder in four C hilean families

Summary Background Glycoprotein VI ( GPVI ), 60–65 k D a, is a major collagen receptor on platelet membranes involved in adhesive and signaling responses. Mice lacking GPVI have impaired platelet response to collagen and defective primary adhesion and subsequent thrombus formation. Complete or partial deficiency of GPVI in humans is a rare condition presenting as a mild bleeding disorder. The defect in most of the reported patients is acquired and associated with other diseases. To date, only two patients have been characterized at the molecular level who carry different compound heterozygous mutations in the GP 6 gene. Objective To report four unrelated patients from non‐consanguineous families who presented with mucocutaneous bleeding. They had absent platelet aggregation and 14 C ‐5‐ HT secretion with collagen, convulxin and collagen‐related peptide. Results Flow cytometry and immunofluorescence‐confocal microscopy showed an absence of GPVI in non‐permeabilized platelets. All the patients had an adenine insertion in exon 6 (c.711_712ins A ), changing the reading frame and generating a premature ‘stop codon’ in site 242 of the protein. The mutation predicts the synthesis of the truncated protein before the trans‐membrane domain, corresponding to a band of ≈49 k D a observed in western blots and in permeabilized platelets by immunofluorescence. Platelet m RNA from all the patients was sequenced and contained the corresponding adenine insertion. Heterozygous relatives had no pathological bleeding, normal response to collagen and convulxin and intermediate membrane expression of GPVI . Conclusions The identification of four unrelated homozygous patients with an identical defect suggests that inherited GPVI deficiency is more frequent than previously suspected, at least in C hile.