We report a family with Bernard-Soulier syndrome with a homozygous mutation within the GPIbβ gene. The proband was a 24-year-old Japanese male who has suffered from life-long bleeding tendency. The patient's sister also had severe bleeding episodes. The proband and the affected sister had no apparent complications including organic or skeletal anomaly, or mental disturbance. They had thrombocytopenia [(35-40) × 109/l] with giant platelets. In addition to platelet size, electron microscopic analysis revealed abnormalities in the internal structures of platelets. Ristocetin-induced platelet aggregation was defective. Flow cytometric analysis and western blot analysis showed that glycoprotein IX was nearly absent in platelets, whereas GPIbα and GPV were detectable. Genetic studies revealed a 13 base pair deletion in the signal peptide-coding sequence of GPIbβ. The deletion would cause a frame-shift, resulting in the appearance of a stop codon following an indifferent polypeptide sequence. Analysis of platelet RNA showed that the mutant GPIbβ gene was transcribed. The propositus and his affected sister were homozygous for the deletion, whereas their unaffected father and mother were heterozygotes. The molecular defects of this family would help understand the relevance of GPIbβ for complex formation of the glycoprotein Ib/IX/V receptor.
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