A common ancestral glycoprotein (GP) 9 1828A>G (Asn45Ser) gene mutation occurring in European families from Australia and Northern Europe with Bernard-Soulier Syndrome (BSS).

Bernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibalpha, GPIbbeta and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX adhesion receptor complex. BSS has been reported in many populations, mostly behaving in an autosomal-recessive manner.While the great majority of BSS mutations are unique to a single individual or family, the GP9 1828A>G Asn45Ser mutation, which we have identified in an undocumented Australian Caucasian, has already been reported in multiple unrelated Caucasian families from various Northern and Central European countries. Haplotype analysis of 19 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 17 1828A>G Asn45Ser homozygotes), showed that 14 of these BSS patients from 11 of the 1828A>G Asn45Ser homozygote families share a common haplotype at the chromosomal region 3' to the GP9 gene. Hence, the results suggest that the GP9 1828A>GAsn45Ser mutation in these families is ancient, and its frequent emergence in the European population is the result of a founder effect rather than recurrent mutational events. Association of the 1828A>G Asn45Ser mutation with variant haplotypes in 4 other Northern European BSS families raised the possibility of a second founder event, or rare recombinations in these families. Additional members from these 'atypical' lineages would need to be screened to resolve this question.

Bernard-Soulier syndrome in a Turkish family.

This report describes the first Turkish family to be diagnosed with Bernard-Soulier syndrome. The family consists of nine members (two parents, three sons and four daughters). The parents were first cousins. The index case, a 22 year-old-man, had a history of haemorrhagic diathesis with thrombocytopenia, giant platelets in the peripheral blood smear and a prolonged bleeding time. Refractory idiopathic thrombocytopenic purpura had been diagnosed elsewhere and a splenectomy had been performed six months previously. Ristocetin agglutination of platelets was defective and flow cytometry analysis of platelet membrane glycoprotein showed markedly reduced expression of glycoprotein lb (2.1%). Bernard-Soulier syndrome was diagnosed. Increased mean platelet volume was found in both parents, one son and three daughters. The other son and daughter were normal.

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 bleeding problem was diagnosed as having BSS based on the prolonged bleeding time, the absence of ristocetin induced platelet aggregations, thrombocytopenia and the presence of giant platelets. Analysis of the platelets of the propositus, a 39-year-old Belgian female, by flow cytometry revealed a decreased expression of the GPIb/IX polypeptides. Western blotting confirmed these results and showed moreover that there was a decreased disulfide bridge formation between GPIb alpha and GPIb beta. After sequence analysis of the GPIb alpha, GPIb beta and GPIX genes, only a mutation in the GPIX gene at position 1826 (A-->G) was identified, changing Asn45-->Ser. Restriction analysis with Fnu4H1 demonstrated that the patient was homozygous for this mutation. As this Asn45-->Ser mutation in the GPIX gene was already found in four unrelated 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 present observation of a decreased disulfide bridge formation between GPIb alpha and GPIb beta shows that GPIX is not only needed for the correct assembly of the complex but might also be needed for the disulfide bridge formation between GPIb alpha and GPIb beta.