BIOCHEMICAL AND MOLECULAR-BASIS OF BERNARD-SOULIER SYNDROME - A REVIEW

Bernard-Soulier syndrome (BSS) is a rare hereditary recessive autosoma l bleeding disorder characterized by a prolonged bleeding time, giant platelets, thrombocytopenia, normal platelet aggregation in response t o ADP and no agglutination in response to ristocetin. This disease is due to absence or abnormality of the platelet membrane glycoprotein GP Ib-IX-V, the receptor for von Willebrand factor. All four genes encodi ng the complex have been cloned and 17 forms of BSS have to date been characterized at the functional, immunological and molecular levels. T he mutations can be divided into two main groups. Firstly, mutations l ocated in leucine rich repeats (LRR), responsible for conformational m odifications of the molecule, in some cases higher sensitivity to prot eases and loss of adhesive function of the receptor, which is expresse d at lower than normal levels at the platelet membrane. When mutations affect the LRR of GPIb alpha, the presence of the other chains varies from normal to residual amounts. When mutations affect the LRR of GPI X, expression of the other chains is strongly diminished, suggesting t hat GPIX plays a major role in the stability of the complex. A second type of mutations leads to synthesis of a truncated molecule lacking t he transmembrane domain and absence of its expression at the platelet surface, while the other chains are present in residual amounts. Expre ssion of recombinant proteins in eukaryotic cells has recently confirm ed the results derived from studies of natural mutations. Separate exp ression of each chain can be obtained, although the presence of all su bunits is required for full expression.