A novel hemizygous Bernard-Soulier Syndrome (BSS) mutation in the amino terminal domain of glycoprotein (GP)Ibbeta--platelet characterization and transfection studies.

Glycoprotein (GP) Ib-V-IX is a unique adhesion receptor complex on platelets. Mutations in GPIbalpha, Ibbeta, and IX can lead to the rare bleeding disorder, Bernard-Soulier Syndrome (BSS). Here, we report a novel hemizygous variant of BSS in which Pro29 in one GPIbbeta allele is substituted by a Leu (GPIbbeta:P29L). Fluoresence in situ hybridisation revealed that the 22q11 locus was deleted from the homologous chromosome. The pedigree was determined and revealed inheritance of the GPIbbeta:P29L allele from the father. Flow cytometry with a range of antibodies detected no expression of GPIb-V-IX on the surface of the patient's platelets. Western blotting revealed an absence of GPIbalpha and GPIbbeta from platelet lysates. Co-expression of GPIbbeta:P29L with normal GPIbalpha and GPIX in a heterologous cell system confirmed that the mutant subunit did not support surface expression of the complex. Interestingly, residual expression of GPIbbeta:P29L anchored in the plasma membrane alone was now seen. This novel BSS mutation expressed in heterologous cells is in agreement with recent in vitro evidence that the correct conformation of the amino terminal region of GPIbbeta is required for normal expression of the intact receptor complex.