ITGB3 – Glanzmann Thrombasthenia

Glanzmann thrombasthenia is a rare autosomal recessive bleeding disorder characterized by defective platelet aggregation due to quantitative or qualitative abnormalities of the integrin αIIbβ3 complex. The β3 subunit, encoded by ITGB3 (HGNC:6156), forms the fibrinogen receptor with αIIb on platelets. Patients present with mucocutaneous bleeding manifestations including gingival bleeding, petechiae, and purpura. The disease is confirmed by absent or reduced αIIbβ3 surface expression and impaired platelet aggregation to multiple agonists.

Genetic evidence for ITGB3 involvement is definitive. Over 150 unrelated probands from more than 70 families harbor biallelic ITGB3 variants, with segregation in consanguineous and non-consanguineous pedigrees (PMID:2014236, PMID:9160670, PMID:25728920). Segregation analysis across >250 affected relatives confirms autosomal recessive inheritance and pathogenicity of missense, nonsense, splice, and frameshift mutations.

The variant spectrum includes missense substitutions (e.g., c.1199G>A (p.Cys400Tyr)), splice-site defects (c.165+1G>T), exon deletions, and truncating alleles (c.1924G>T (p.Glu642Ter)). Founder mutations have been described in Iraqi-Jewish (c.2031_2041del (p.Asp677fs)) and Jordanian families (c.1645T>C (p.Cys549Arg)) (PMID:2014236, PMID:18064323). Recurrent alleles in distinct populations enable carrier screening and prenatal diagnosis.

Functional assays corroborate genetic findings. The p.Ser778Pro (formerly Ser-752Pro) variant uncouples platelet activation from αIIbβ3 up-regulation and bidirectional signaling in transfected cells, with preserved ligand-binding sites but defective inside-out and outside-in signaling (PMID:1438206, PMID:8080992). Mutagenesis of β3 cytoplasmic tyrosines (Y747F) abolishes stimulated adhesion, highlighting critical regulatory motifs (PMID:9353346).

No credible conflicting evidence has emerged to dispute the ITGB3–Glanzmann thrombasthenia association. The concordance of genotype, segregation, and mechanistic defect in integrin biosynthesis and signaling across decades supports a conclusive relationship.

ITGB3 is therefore definitively implicated in Glanzmann thrombasthenia. Molecular testing for ITGB3 variants enables precise diagnosis, risk assessment, and genetic counseling. The established genotype–phenotype framework supports variant interpretation and informed therapeutic decisions.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1991 • The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. PMID:2014236
• Blood • 1997 • Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. PMID:9160670
• Human mutation • 2015 • Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort PMID:25728920
• 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
• Blood • 1994 • A point mutation in the integrin beta 3 cytoplasmic domain (S752→P) impairs bidirectional signaling through alpha IIb beta 3 (platelet glycoprotein IIb-IIIa). PMID:8080992
• The Journal of Biological Chemistry • 1997 • Requirement of integrin beta3 tyrosine 747 for beta3 tyrosine phosphorylation and regulation of alphavbeta3 avidity. PMID:9353346

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