Homozygous Pro74 -> Arg mutation in the platelet glycoprotein Ib beta geneassociated with Bernard-Soulier syndrome

Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder due to quantitative or qualitative abnormalities in the glycoprotein (GP) I b/IX/V complex, the platelet receptor for von Willebrand factor. This compl ex is composed of four subunits, GPIb alpha, GPIb beta, GPIX and GPV. We de scribe here the genetic basis of the disorder in a patient with BSS. Flow c ytometric analysis of the patient's platelets showed greatly reduced GPIb a lpha and GPIX surface expression. Immunoblot analysis disclosed absence of GPIb alpha, GPIb beta and GPIX in the platelets. DNA sequencing analysis re vealed a novel missense mutation in the GPIb beta gene that converts Pro (C CG) to Arg (CGG) at residue 74. Homozygosity of the mutation was confirmed by allele-specific restriction analysis, chromosome 22 microsatellite analy sis and quantitative Southern blotting. The mutant GPIb beta was normally t ranscribed. Transient transfection studies confirmed that mutant GPIb beta impairs surface expression of GPIb/IX. showing that the mutation is respons ible for a BSS phenotype observed in the patient.