BERNARD-SOULIER SYNDROME KARLSTAD - TRP 498-]STOP MUTATION RESULTING IN A TRUNCATED GLYCOPROTEIN IB-ALPHA THAT CONTAINS PART OF THE TRANSMEMBRAMOUS DOMAIN

In Bernard-Soulier syndrome, a hereditary bleeding disorder, the plate lets are deficient in the glycoprotein (GP) Ib-M-V complex, a major re ceptor for the von Willebrand factor. The components of the complex ar e encoded by separate genes. Patients with this syndrome have a variab le expression level of the receptor protein on platelets depending on the specific genetic abnormality. We describe a patient with life-long bleeding symptoms, who is homozygous for a unique stop mutation, Trp 498 --> Stop in the GPIb alpha gene, resulting in a truncated GPIb alp ha polypeptide chain. In contrast to previously reported truncated for ms of GPIb alpha, this form contains a portion of the transmembranous domain as well as the juxtamembranous cysteines engaged in a disulphid e bond with GPIb beta. Flow cytometry with GPIb alpha antibodies demon strated the presence of GPIb on the patient's platelets, although in r educed amounts compared to normal controls. GPIX was similarly detecta ble. Immunoblotting demonstrated that the patient synthesized a trunca ted GFIb alpha of the expected size of 130K, which was, however, sensi tive to proteolysis. These studies show that GPIb alpha lacking the in tracytoplasmic tail can be expressed at the platelet surface provided elements of the transmembranous domain are present.