Thromb Haemost 2005; 94(03): 599-605
DOI: 10.1160/TH05-03-0165
Platelets and Blood Cells
Schattauer GmbH

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)

Hai Po Helena Liang
1   Northern Blood Research Centre, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, Australia
2   2Discipline of Medicine, University of Sydney, Camperdown, Australia
,
Marie-Christine Morel-Kopp
1   Northern Blood Research Centre, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, Australia
,
Jeannine M. Clemetson
3   Theodor-Kocher Institute, University of Berne, Berne, Switzerland
,
Kenneth J. Clemetson
3   Theodor-Kocher Institute, University of Berne, Berne, Switzerland
,
Riitta Kekomaki
4   Finnish Red Cross Blood Transfusion Service, Helsinki, Finland
,
Hartmut Kroll
5   Institute for Clinical Immunology and Transfusion Medicine, Giessen, Germany
,
Katerina Michaelides
6   Haemostasis and Thrombosis Research, MRC Clinical Sciences Center, Hammersmith Hospital, London, United Kingdom
,
Edward G. D. Tuddenham
6   Haemostasis and Thrombosis Research, MRC Clinical Sciences Center, Hammersmith Hospital, London, United Kingdom
,
Karen Vanhoorelbeke
7   Laboratory for Thrombosis Research, IRC, K.U. Leuven Campus Kortrijk, Kortrijk, Belgium
,
Christopher M. Ward
1   Northern Blood Research Centre, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, Australia
2   2Discipline of Medicine, University of Sydney, Camperdown, Australia
› Author Affiliations
Financial support: H. Liang is a recipient of the Australian Postgraduate Award from the University of Sydney. J. M. Clemetson and K. J. Clemetson would like to acknowledge support from the Swiss National Science Foundation Grant No. 31-063868.00.
Further Information

Publication History

Received: 08 March 2005

Accepted after major revision: 09 June 2005

Publication Date:
07 December 2017 (online)

Summary

Bernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibα, GPIbβ 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.

K. Vanhoorelbeke is a postdoctoral fellow of the Fonds voor Wetenschappelijk Onderzoek, Vlaanderen, Belgium.


 
  • References

  • 1 López JA, Andrews RK, Afshar-Kharghan V. et al. Bernard-Soulier syndrome.. Blood 1998; 91: 4397-418.
  • 2 Berndt MC, Shen Y, Dopheide SM. et al. The vascular biology of the glycoprotein Ib-IX-V complex.. Thromb Haemost 2001; 86: 178-88.
  • 3 Simsek S, Admiraal LG, Modderman PW. et al. Identification of a homozygous single base pair deletion in the gene coding for the human platelet Glycoprotein Ibα causing Bernard-Soulier syndrome.. Thromb Haemost 1994; 72: 444-9.
  • 4 Kanaji T, Okamura T, Kuroiwa M. et al. Molecular and genetic analysis of two patients with Bernard-Soulier syndrome – identification of new mutations in Gly-coprotein Ibα gene.. Thromb Haemost 1997; 77: 1055-61.
  • 5 De La Salle C, Baas M-J, Lanza F. et al. A three-base deletion removing a leucine residue in a leucine-rich repeat of platelet Glycoprotein Ibα associated with a variant of Bernard-Soulier syndrome (Nancy I).. Br J Haematol 1995; 89: 386-96.
  • 6 Gonzalez-Manchon C, Butta N, Iruin G. et al. Disruption of the Cys5-Cys7 disulfide bridge in the platelet Glycoprotein Ibβ prevents the normal maturation and surface exposure of GPIb-IX complexes.. Thromb Haemost 2003; 90: 456-64.
  • 7 Moran N, Morateck PA, Deering A. et al. Surface expression of Glycoprotein Ibα is dependent on Glycoprotein Ibβ: evidence from a novel mutation causing Bernard-Soulier syndrome.. Blood 2000; 96: 532-9.
  • 8 Strassel C, Pasquet J-M, Alessi M-C. et al. A novel missense mutation shows that GPIbβ has a role in controlling the processing and stability of the platelet GPIb-IX adhesion receptor.. Biochemistry 2003; 42: 4452-62.
  • 9 Rivera CE, Villagra J, Riordan M. et al. Identification of a new mutation in platelet Glycoprotein IX (GPIX) in a patient with Bernard-Soulier syndrome.. Br J Haematol 2001; 112: 105-108.
  • 10 Kunishima S, Tomiyama Y, Honda S. et al. Cys97→Τyr mutation in the Glycoprotein IX gene as-sociated with Bernard-Soulier syndrome.. Br J Haematol 1999; 107: 539-45.
  • 11 Okan V, Araz M, Camci C. et al. Bernard-Soulier syndrome in a Turkish family.. Int J Clin Pract 2002; 56: 546-8.
  • 12 Savoia A, Balduini CL, Savino M. et al. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome.. Blood 2001; 97: 1330-5.
  • 13 Wright SD, Michaelides K, Johnson DJD. et al. Double heterozygosity for mutations in the platelet Glycoprotein IX gene in three siblings with Bernard- Soulier syndrome.. Blood 1993; 81: 2339-47.
  • 14 Clemetson JM, Kyrle PA, Brenner B. et al. Variant Bernard-Soulier Syndrome associated with a homozygous mutation in the leucine-rich domain of Glycoprotein IX.. Blood 1994; 84: 1124-31.
  • 15 Koskela S, Javela K, Jouppila J. et al. Variant BernardSoulier syndrome due to homozygous asn45ser mutation in the platelet Glycoprotein (GP) IX in seven patients of five unrelated Finnish families.. Eur J Haematol 1999; 62: 256-64.
  • 16 Donnér M, Karpman D, Kristoffersson AC. et al. Recurrent mutation Asn45 → Ser of Glycoprotein IX in Bernard-Soulier syndrome.. Eur J Haematol 1996; 57: 178-9.
  • 17 Vanhoorelbeke K, Schlammadinger A, Delville JP. et al. Occurrence of the Asn45Ser mutation in the GPIX gene in a Belgian patient with Bernard Soulier syndrome.. Platelets 2001; 12: 114-20.
  • 18 Sachs UJH, Kroll H, Matzdorff AC. et al. Bernard- Soulier syndrome due to the homozygous Asn-45Ser mutation in GPIX: an unexpected, frequent finding in Germany.. Br J Haematol 2003; 123: 127-31.
  • 19 Wang WYS, Barratt BJ, Clayton DG. et al. Genomewide association studies: Theoretical and practical concerns.. Nat Rev Genet 2005; 6: 109-18.
  • 20 Sae-Tung G, Dong J-F, López JA. Biosynthetic defect in platelet Glycoprotein IX mutants associated with Bernard-Soulier syndrome.. Blood 1996; 87: 1361-7.
  • 21 Norio R. The Finnish Disease Heritage III: the individual diseases.. Hum Genet 2003; 112: 470-526.
  • 22 Castoldi E, Lunghi B, Mingozzi F. et al. New coagulation Factor V gene polymorphisms define a single and infrequent haplotype underlying the Factor V Leiden mutation in Mediterranean populations and Indians.. Thromb Haemost 1997; 78: 1037-41.