A 13-bp deletion in alpha(IIb) gene is a founder mutation that predominates in Palestinian-Arab patients with Glanzmann thrombasthenia.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by lack or dysfunction of alpha(IIb)beta3 in platelets. GT is relatively frequent in highly inbred populations. We previously identified a 13-bp deletion in the alpha(IIb) 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 alpha(IIb)beta3 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 alpha(IIb)beta3 maturation. Substitution of Trp110, but not of Cys107, prevented fibrinogen binding. The other Palestinian patients harbored three novel mutations: G2374 deletion in alpha(IIb) gene, TT1616-7 deletion in beta3 gene, and IVS14: -3C --> G in beta3 gene. The latter mutation caused cryptic splicing predicting an extended cytoplasmic tail of beta3 and was expressed as dysfunctional alpha(IIb)beta(3). None of 15 unrelated Jordanian patients carried any of the described mutations.
Rosenberg
N
N
Amalia Biron Research Institute of Thrombosis and Hemostasis, The Chaim Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Hauschner
H
H
Peretz
H
H
Mor-Cohen
R
R
Landau
M
M
Shenkman
B
B
Kenet
G
G
Coller
B S
BS
Awidi
A A
AA
Seligsohn
U
U
D019943:Amino Acid Substitution; D000818:Animals; D018912:Arabs / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D006224:Cricetinae; D004252:DNA Mutational Analysis; D005340:Fibrinogen / Q000378:metabolism; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics; D007597:Jordan / Q000208:ethnology; D017720:Molecular Epidemiology; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics*; D017384:Sequence Deletion; D013915:Thrombasthenia / Q000208:ethnology / Q000235:genetics*; D014161:Transduction, Genetic
D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb; D005340:Fibrinogen