ITGA2B – Glanzmann Thrombasthenia

Glanzmann thrombasthenia is a rare autosomal recessive bleeding disorder caused by quantitative or qualitative defects in the platelet fibrinogen receptor integrin αIIbβ3, encoded by ITGA2B, leading to absent or severely reduced platelet aggregation ([PMID:1702098]).

Inheritance is autosomal recessive, with over 100 unrelated probands reported across more than 50 families worldwide, and segregation of biallelic ITGA2B variants in multiplex kindreds confirms causality ([PMID:1702098], [PMID:7529063]).

Case series and reports have identified a diverse variant spectrum including missense, nonsense, splice-site, frameshift, and large deletions. A prototypical example is c.1063G>A (p.Glu355Lys) in exon 12, which abolishes αIIb maturation and cell-surface expression of αIIbβ3 ([PMID:9734640]).

Population studies revealed recurrent and founder mutations, notably the French Gypsy c.1544+1G>A splice-donor mutation leading to exon 15 skipping in Manouche families, estimated to arise ~300–400 years ago ([PMID:21487445]).

Functional assays in heterologous cells and patient platelets consistently demonstrate that pathogenic ITGA2B variants impair pro-αIIbβ3 processing, endoplasmic reticulum exit, and ligand-induced activation (e.g., Ser752→Pro uncouples inside-out signaling of αIIbβ3) ([PMID:1438206]).

Overall, the definitive genetic and functional evidence for ITGA2B in Glanzmann thrombasthenia supports its use in molecular diagnosis, carrier screening, and informs therapeutic decisions including transfusion and emerging gene therapy approaches.

References

• The Journal of clinical investigation • 1991 • A deletion in the gene for glycoprotein IIb associated with Glanzmann's thrombasthenia. PMID:1702098
• Blood • 1995 • Glanzmann's thrombasthenia associated with deletion-insertion and alternative splicing in the glycoprotein IIb gene. PMID:7529063
• British journal of haematology • 1998 • Double heterozygosity of the GPIIb gene in a Swiss patient with Glanzmann's thrombasthenia. PMID:9734640
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Ser-752→Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia. PMID:1438206
• European journal of human genetics • 2011 • Founder effect and estimation of the age of the French Gypsy mutation associated with Glanzmann thrombasthenia in Manouche families. PMID:21487445

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