Introduction

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          Bernard-Soulier syndrome is a rare disorder that results in a deficiency of glycoprotein Ib and affects 1 out of every 1 million people. Glycoprotein Ib is the receptor for von Willebrand factor which causes proteins to stick to one another. This function is extremely important in blood clotting, specifically in the process of platelet adhesion to wound sites to plug vascular injuries. When glycoprotein Ib is deficient, von Willebrand factor cannot be activated and platelet adhesion does not occur, resulting in excessive bleeding, bruising, and hemorrhaging.

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          Three genes, when mutated, have been identified to cause Bernard-Soulier syndrome: GP1BA, GP1BB, and GP9. These genes code for the GPIba, GPIbb, and GPIX subunits of Glycoprotein Ib, respectively (Alsahafi, 2018). These mutations cause expression of glycoprotein Ib to be significantly reduced or completely eliminated on the cell membrane. This prevents platelet aggregation at vascular injury sites because the glycoprotein Ib can not activate the von Willebrand factor as mentioned before. Mutations in the GP1BB and GP9 genes resulted in glycoprotein Ib expression to be less than 10% whereas mutations in the GP1BA gene was less severe with GPIb expression lowered to only 20% (Savoia et al, 2010).

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          Missense mutations in these genes cause the GPIb protein to be slightly mis-folded and results in a destabilized protein conformation. In its standard conformation, an Asparagine amino acid located at the 110th spot in the sequence is completely buried with its side chain pointing towards the hydrophobic core. When mutated, this Asn110 is substituted with a charged amino acid that would require a large amount of energy to keep buried, thus resulting in a very unstable fold. It just so happens that Asn110 is located within the binding site to the von Willebrand factor, meaning that when mutated, it significantly reduces the ability of GPIb to bind to vWF (Savoia et al, 2010).