A missense mutation (Tyr88 to Cys) in the platelet membrane glycoprotein Ib beta gene affects GPIb/IX complex expression - Bernard-Soulier syndrome in the homozygous form and giant platelets in the heterozygous form

This study examined the Molecular basis of a missense mutation of the plate let glycoprotein (GP) Ib beta gene in two families. In the propositus with a novel form of Bernard-Soulier syndrome (BSS) from Family I, only GPIb alp ha was detectable in reduced amounts on platelet surfaces by flow cytometry . There were no GPIX or GPIb beta found by immunoblotting. DNA sequencing a nalysis showed a homozygous mutation in the GPIb beta gene which changed Ty r (TAC) to Cys (TGC) at residue 88. Her parents were heterozygous for Tyr88 Cys in the GPIb beta gene. In transient transfection studies on 293T cells, both Tyr88Cys and Tyr88Ala mutations suppressed the expression of GPIb/IX complexes. in addition, Tyr88Cys GPIb beta mutation was found to exert a do minant negative effect on the GPIb alpha expression. Five individuals from Family II, four of whom reported elsewhere as having giant platelet disorders with normal aggregation (BLOOD, 1997 89: 2404) and one newly analyzed in this study, were heterozygous for Tyr88Cys in the GP Ib beta gene. Microsatellite analysis of chromosome 22 showed a common hapl otype in 8 of the individuals with Tyr88Cys mutations in Families I and II. Tyr88 in the GPIb beta gene plays a significant role in the GPIb/IX expres sion; the defect causes BSS in a homozygous form and possibly giant platele ts in a heterozygous form.