A 13-bp deletion in αIIb gene is a founder mutation that predominates in Palestinian-Arab patients with Glanzmann thrombasthenia

N. Rosenberg, H. Hauschner, H. Peretz, R. Mor-Cohen, M. Landau, B. Shenkman, G. Kenet, B. S. Coller, A. A. Awidi, U. Seligsohn

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by lack or dysfunction of αIIbβ 3 in platelets. GT is relatively frequent in highly inbred populations. We previously identified a 13-bp deletion in the αIIb gene that causes in-frame deletion of six amino acids in three Palestinian GT patients. In this study, we determined the molecular basis of GT in all known Palestinian patients, examined whether Jordanian patients harbor the same mutations, analyzed whether there is a founder effect for the 13-bp deletion, and determined the mechanism by which the 13-bp deletion abolishes αIIbβ3 surface expression. Of 11 unrelated Palestinian patients, eight were homozygous for the 13-bp deletion that displayed common ancestry by haplotype analysis, and was estimated to have occurred 300-600 years ago. Expression studies in baby hamster kidney cells showed that substitution of Cys107 or Trp110 located within the deletion caused defective αIIbβ3 maturation. Substitution of Trp110, but not of Cys107, prevented fibrinogen binding. The other Palestinian patients harbored three novel mutations: G2374 deletion in αIIb gene, TT1616-7 deletion in β3 gene, and IVS14: -3C → G in β3 gene. The latter mutation caused cryptic splicing predicting an extended cytoplasmic tail of β3 and was expressed as dysfunctional αIIbβ3. None of 15 unrelated Jordanian patients carried any of the described mutations.

Original languageEnglish
Pages (from-to)2764-2772
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume3
Issue number12
DOIs
StatePublished - Dec 2005
Externally publishedYes

Keywords

  • Founder effect
  • Integrin αβ
  • Variant Glanzmann thrombasthenia

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