Occurrence of the Asn45Ser mutation in the GPIX gene in a Belgian patient with Bernard Soulier syndrome

Bernard Soulier Syndrome (BSS) is a rare inherited bleeding disorder caused by a defect in the glycoprotein (GP)Ib/IX/V complex. A patient with a blee ding problem was diagnosed as having BSS based on the prolonged bleeding ti me, the absence of ristocetin induced platelet aggregations, thrombocytopen ia and the presence of giant platelets. Analysis of the platelets of the pr opositus, a 39-year-old Belgian female, by flow cytometry revealed a decrea sed expression of the GPIb/IX polypeptides. Western blotting confirmed thes e results and showed moreover that there was a decreased disulfide bridge f ormation between GPIb alpha and GPIb beta. After sequence analysis of the G PIba, GPIb beta and GPIX genes, only a mutation in the GPIX gene at positio n 1826 (A-->G) was identified, changing Asn45-->Ser. Restriction analysis w ith Fnu4H1 demonstrated that the patient was homozygous for this mutation, As this Asn45-->Ser mutation in the GPIX gene was already found in four unr elated families, i.e. in a British, Austrian, Swedish and Finnish one, the occurrence of this mutation in a Belgian patient supports the hypothesis of Koskela et al, (1999) that the Asn45Ser mutation in GPIX appears to be an ancient mutation shared by northern and central European populations. Our p resent observation of a decreased disulfide bridge formation between GPIb a lpha and GPIb beta shows that GPIX is not only needed for the correct assem bly of the complex but might also be needed for the disulfide bridge format ion between GPIb alpha and GPIb beta.