A Common Ancestral Glycoprotein (GP) IX Gene Mutation (Asn45Ser) Causes Bernard-Soulier Syndrome (BSS) in European Families from Northern Europe and Australia

Abstract number: OR222

Liang^1,2 HPH, Morel-Kopp¹ MC, Clemetson³ KJ, Kekomaki⁴ R, Kroll⁵ H, Michaelides⁶ K, Tuddenham⁶ EGD, Vanhoorelbeke⁷ K, Ward¹ CM

^{1,2 11}Northern Blood Research Centre, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, Australia ³³Theodor-Kocher Institute, Switzerland ⁴⁴Finnish Red Cross Blood Transfusion Service, Helsinki, Finland ⁵⁵Institute for Clinical Immunology and Transfusion Medicine, Giessen, Germany ⁶⁶Haemostasis and Thrombosis Research, MRC Clinical Sciences Center, Hammersmith Hospital, London, UK ⁷⁷K.U.Leuven Campus Kortrijk, Interdisciplinary Research Center, Kortrijk, Belgium

Bernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations within the Glycoprotein (GP) Iba, GPIbb and GPIX genes encoding for subunits of the platelet GPIb-V-IX adhesion receptor. BSS has been reported in many populations, and is typically inherited in an autosomal-recessive manner. While most of the BSS mutations were found to be unique to a single individual or family, an Asn45Ser single nucleotide substitution, within the highly conserved leucine-rich repeat region of GPIX, has been reported in several unrelated Caucasian families from various countries across Northern and Central Europe. Recently, we have identified this same mutation in an Australian patient of Caucasian origin. Consequently, we performed a haplotype study to determine whether the Asn45Ser mutation is an ancient ‘mutation’ in the European population, or indicates a ‘hot-spot’ for mutagenesis in the GPIX gene. The haplotypes of Asn45Ser carriers and 100 Caucasian controls were established by single nucleotide polymorphism screening using allele-specific PCR and DHPLC techniques. Haplotype analysis of 18 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 16 Asn45Ser homozygotes), showed that 13 (72%) of these BSS patients from 11 of the Asn45Ser homozygote families share a common haplotype at the chromosomal region 3' to the GPIX gene. Hence, the results suggest that the GPIX Asn45Ser 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. The GPIX Asn45Ser mutation may have arisen separately in the 4 remaining Northern European BSS families with ‘atypical’ haplotype patterns; recombination events are less likely explanation, given the close proximity of the genetic markers we have utilized.