Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort

Human Mutation
A NurdenChristine Vinciguerra

Abstract

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturat...Continue Reading

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Citations

Jan 21, 2016·Blood·Elisa BianchiRossella Manfredini
Dec 30, 2016·Platelets·Diane Nugent, Thomas Kunicki
Apr 4, 2018·British Journal of Haematology·Mathieu FioreMarie-Christine Alessi
Oct 31, 2017·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Ahmad KazemiFereydoun Ala
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Oct 1, 2019·Journal of Thrombosis and Haemostasis : JTH·Benoit GuilletAlan T Nurden
Jun 20, 2020·International Journal of Laboratory Hematology·Tooba AliShagufta Khaliq
Nov 11, 2017·Platelets·Alan T Nurden, Xavier Pillois
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May 1, 2021·International Journal of Molecular Sciences·Verónica Palma-BarquerosJosé Rivera
Dec 24, 2021·Hämostaseologie·Doris BoeckelmannBarbara Zieger

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