Thromb Haemost 2002; 87(06): 1034-1042
DOI: 10.1055/s-0037-1613129
Review Article
Schattauer GmbH

Glanzmann’s Thrombasthenia: Identification of 19 New Mutations in 30 Patients

Giovanna D’Andrea
1   Unità di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo; Genetica Medica, Università di Foggia; and Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
,
Donatella Colaizzo
1   Unità di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo; Genetica Medica, Università di Foggia; and Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
,
Gennaro Vecchione
1   Unità di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo; Genetica Medica, Università di Foggia; and Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
,
Elvira Grandone
1   Unità di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo; Genetica Medica, Università di Foggia; and Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
,
Giovanni Di Minno
1   Unità di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo; Genetica Medica, Università di Foggia; and Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
,
Maurizio Margaglione
1   Unità di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo; Genetica Medica, Università di Foggia; and Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
,
the GLAnzmann’s Thrombasthenia Italian Team (GLATIT) › Author Affiliations
Further Information

Publication History

Received 10 August 2001

Accepted after resubmission 07 February 2002

Publication Date:
08 December 2017 (online)

Summary

Glanzmann’s thrombasthenia (GT) is a genetically heterogeneous autosomal recessive syndrome associated with a bleeding tendency. To elucidate molecular basis of GT we have screened for mutations 30 GT patients. On the whole, 21 different candidate causal mutations, 17 in the αIIb and 4 in the β3 gene have been found. Only two (αIIb Pro145Ala and IVS3(−3)-418del) have been previously reported. Nine mutations (42.9%) were likely to produce truncated proteins, whereas the remaining 12 were missense mutations that affected highly conserved residues in αIIb and β3 genes. Six mutations were found in different patients suggesting a possible founder effect. The wide spectrum of expressivity, ranging from mild to severe also among patients carrying the same mutations, provided evidence for a role of different loci or circumstantial factors. In conclusion, we have identified a spectrum of unreported mutations that may be of value to unravel the role of specific regions of αIIb and β3 genes.

* The other contributors to this study are listed in the Appendix


 
  • References

  • 1 Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive integrin. Cell 1991; 65: 356-66.
  • 2 Caen JP, Castaldi PA, Leclerc JC. et al. Congenital bleeding disorders with long bleeding time and normal platelet count. I. Glanzmann’s thrombasthenia (reports on fifteen patients). Am J Med 1966; 41: 4-26.
  • 3 George JN, Nurden AT, Phillips DR. Molecular defects in interactions of platelets with the wessel wall. N Engl J Med 1984; 311: 1084-98.
  • 4 Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIb-IIIa complex. Blood 1988; 71: 831-43.
  • 5 Caen JP. Glanzmann’s thrombasthenia. Clin Haematol 1972; 01: 383-92.
  • 6 George JN, Caen JP, Nurden AT. Glanzmann’s thrombasthenia: the spectrum of clinical disease. Blood 1990; b75: 1383-95.
  • 7 Margaglione M, D’Andrea G, Grandone E, Brancaccio V, Amoriello A, Di Minno G. Compound heterozygosity (554-589 del, C515-T transition) in the platelet glycoprotein Iba gene in a patient with a severe bleeding tendency. Thromb Haemost 1999; 81: 486-92.
  • 8 Heidenreich R, Eisman R, Surrey S. et al. Organization of the gene for platelet glycoprotein IIb. Biochemistry 1990; 29: 1232-44.
  • 9 Villa-Garcia M, Li L, Riely G, Bray PF. Isolation and characterization of a TATA-less promoter for the human beta 3 integrin gene. Blood 1994; 83: 668-76.
  • 10 Zimrin AB, Gidwitz S, Lord S. et al. The genomic organization of platelet glycoprotein IIIa. J Biol Chem 1990; 265: 8590-5.
  • 11 Margaglione M, Santacroce R, Colaizzo D. et al. A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenemia due to abnormal RNA splicing. Blood 2000; 96: 2501-5.
  • 12 Springer TA. Folding of the N-terminal, ligand-binding region of integrin α-subunits into a β-propeller domain. Proc Natl Acad Sci USA 1997; 94: 65-72.
  • 13 Calvete JJ. On the structure and function of platelet integrin αIIbβ3, the fibrinogen receptor. Proc Soc Exp Biol Med 1995; 208: 346-60.
  • 14 Xiong J-P, Sthele T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnout MA. Crystal structure of the extracellular segment of integrin αVβ3 . Science 2001; 294: 339-45.
  • 15 Calvete JJ, Henschen A, Gonzalez-Rodriguez J. Assignment of disulphide bonds in human platelet GPIIIa. Biochem J 1991; 274: 63-71.
  • 16 Krawczak M, Cooper DN. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet 1991; 86: 425-41.
  • 17 Darvasi A, Kerem B. Deletion and insertion mutations in short tandem repeats in the coding regions of human genes. Eur J Hum Genet 1995; 03: 14-20.
  • 18 Rodenhiser D, Chakraborty P, Andrews J. et al. Heterogenous point mutations in BRCA1 breast cancer susceptibility gene occurs in high frequency at the site of homonucleotide tracts, short repeats and hypermethylatable CpG/CpNpG motifs. Oncogene 1996; 12: 2623-9.
  • 19 Denissenko MF, Chen JX, Tang MS, Pfeifer GP. Cytosine methylation determines hotspots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA 1997; 94: 3893-8.
  • 20 Newman PJ, Seligsohn U, Lyman S, Coller BS. The molecular genetic basis of Glanzmann thromboasthenia in Iraqui-Jewish and Arab populations in Israel. Proc Natl Acad Sci USA 1991; 88: 3160-4.
  • 21 Basani RB, French DL, Vilaire G. et al. A naturally occurring mutation near the amino terminus of αIIb defines a new region involved in ligand binding to αIIbβ3 . Blood 2000; 95: 180-8.
  • 22 Baker EK, Collins ETozer, Pfaff M, Shattil AJ, Loftus JC, Ginsberg MH. A genetic analysis of integrin function. Glanzmann thromboasthenia in vitro. Proc Natl Acad Sci USA 1997; 94: 1973-8.
  • 23 Shattil SJ, Kashiwagi H, Pampori N. Integrin signalling: the platelet paradigm. Blood 1998; 91: 2645-57.
  • 24 Neerman-Arbez M, Hornsberger A, Antonarakis SE, Morris MA. Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital afibrinogenemia. J Clin Invest 1999; 103: 215-8.
  • 25 Kemball-Cook G, Tuddenham EG. The Factor VIII Mutation Database on the World Wide Web: the haemophilia A mutation, search, test and resource site. HAMSTeRS update (version 3.0). Nucleic Acid Res 1997; 25: 128-32.