Molecular characterization of two mutations in platelet glycoprotein (GP) Ib alpha in two Finnish Bernard-Soulier syndrome families

Bernard-Soulier syndrome (BSS) is a rare hereditary bleeding disorder and m acrothrombocytopenia which is caused by a defect in the platelet glycoprote in Ib/IX/V (GP Ib/IX/V) complex, the receptor for von Willebrand factor and thrombin. Here we report the molecular basis of the classical form of BSS in two unrelated Finnish patients, both with a life-long history of severe bleeding. Flow cytometry and immunoblotting showed no expression of GP Ib/I X, GP Ib alpha, GP Ib beta or GP IX (less than 10%) in the patients' platel ets. No expression of GP V (<10%) was observed in propositus 1, but a resid ual amount was found in propositus 2 (24%). DNA sequencing analysis reveale d that propositus 1 was compound heterozygous for a two-base-pair deletion at Tyr505(TAT) and a point mutation Leu129(CTC)Pro(CCC) in the GP Ib alpha gene. Propositus 2 was homozygous for the Tyr505(TAT) deletion. The nine re latives who were heterozygous for either of the mutations also had low leve ls of GP Ib alpha (74-90%). Hence, Bernard-Soulier patients homozygous or c ompound heterozygous for Tyr505(TAT) are severely affected. Interestingly, both mutations have independently been found in three other families in pre vious reports, suggesting their ancient age or mutational 'hot spot'.