Summary

This study examined the molecular basis of a missense mutation ofthe platelet glycoprotein (GP) Ibβ gene in two families. In the proposituswith a novel form of Bernard-Soulier syndrome (BSS) fromFamily I, only GPIbα was detectable in reduced amounts on plateletsurfaces by flow cytometry. There were no GPIX or GPIbβ found byimmunoblotting. DNA sequencing analysis showed a homozygousmutation in the GPIbβ gene which changed Tyr (TAC) to Cys (TGC) atresidue 88. Her parents were heterozygous for Tyr88Cys in the GPIbβgene. In transient transfection studies on 293T cells, both Tyr88Cys andTyr88Ala mutations suppressed the expression of GPIb/IX complexes.In addition, Tyr88Cys GPIbβ mutation was found to exert a dominantnegative effect on the GPIbα expression.Five individuals from Family II, four of whom reported elsewhere ashaving giant platelet disorders with normal aggregation (BLOOD,1997; 89: 2404) and one newly analyzed in this study, were heterozygousfor Tyr88Cys in the GPIbβ gene. Microsatellite analysis of chromosome22 showed a common haplotype in 8 of the individuals withTyr88Cys mutations in Families I and II. Tyr88 in the GPIbβ geneplays a significant role in the GPIb/IX expression; the defect causesBSS in a homozygous form and possibly giant platelets in a heterozygousform.