Compound heterozygosity of the GPIbalpha gene associated with Bernard-Soulier syndrome

Abstract

We report the molecular genetic analysis of the Bernard-Souliersyndrome (BSS) phenotype in two related patients showing absence ofglycoprotein (GP) Ib and detectable amounts of GPIX on the plateletsurface, and a truncated form of GPIb in solubilized platelets andplasma. They both were compound heterozygotes for the GPIbα gene:a maternal allele with a T insertion at position 1418 causing a translationalframeshift and premature polypeptide termination, and a paternalallele with a T715A substitution changing Cys209 to Ser. Heterozygotesfor either one of these mutations were asymptomatic. Transienttransfection of cells coexpressing GPIbβ and GPIX failed to detectsurface expression of the GPIbα mutants. Cells transfected with[1418insT]GPIbα-cDNA showed a truncated protein of the predictedsize in both cell lysate and conditioned medium, indicating theinability of the mutant protein to anchor the plasma membrane. Incontrast, transfection of [T715A]GPIbα-cDNA yield a mutated proteinbarely detectable in the cell lysate and absent in the medium, indicatingthat the loss of Cys209 renders GPIbα more vulnerable to proteolysisand unable to undergo the normal secretory pathway. Our findingsindicate that the additive effects of both mutations are responsible forthe BSS phenotype of the patients