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

Abstract

Summary. Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by lack or dysfunction of αIIbβ3 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.

An intracytoplasmic β3 Leu718 deletion in a patient with a novel platelet phenotype

“…6,11,20,21 Neither patient exhibited MTP, which was present in a third family with a novel ITGB3 intronic mutation and frameshift that extended the b3 cytoplasmic domain by 40 amino acids and which locked aIIbb3 in a resting state by distancing the talin and kindlin-3 binding sites from the membrane. 22,23 Genetic variants affecting aIIb and b3 cytoplasmic domains that produce MTP show that the mutations result in an altered cytoskeletal architecture and reduced proplatelet formation. 2,13,24 Our ITGB3 L718del (with loss of synchronization between the intracytoplasmic tail of b3 with that of aIIb) resulted in moderate MTP, decreased activation of aIIbb3 at the platelet surface, and abnormally large a-granules and represents a novel phenotype.…”

L718P mutation in the membrane-proximal cytoplasmic tail of 3 promotes abnormal IIb 3 clustering and lipid microdomain coalescence, and associates with a thrombasthenia-like phenotype

“…Two of them, R995Q in αIIb 11 and D723H in β3, 12 disrupt a conserved salt bridge that stabilizes the interaction between the membrane-proximal regions of the α and β subunits. 13 Three other mutations in the β3 cytoplasmic domain, R724STOP, 14 S752P, 15 and IVS14-3C>G, 16 were found in homozygosis associated with variant forms of Glanzmann's thrombasthenia caused by defective activation of αIIbβ3.…”

Founder effect and estimation of the age of the French Gypsy mutation associated with Glanzmann thrombasthenia in Manouche families

“…19 Founder effects have also been previously identified for GT in 11 unrelated Palestinian patients carrying the same 13-bp deletion in the ITGA2B gene, and in 6 Jordanian families carrying a C549R mutation in b3. 23,24 The Jordanian C549R mutation probably occurred more recently because the haplotype associated with the C549R mutation was conserved over a distance of 4.5 Mb, while the common haplotype associated with the Palestinian 13-bp deletion was only of 350 kb. Analyzing the closest loci showing recombination events with the mutations yielded an age estimate of 300-600 years for the 13-bp deletion in Palestinian patients and 120-150 years for the C549R in Jordanian ones.…”