GP1BB – Bernard-Soulier syndrome

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder caused by deficiency of the platelet GPIb-IX-V receptor complex, essential for von Willebrand factor–mediated adhesion. GP1BB encodes the GPIbβ subunit, and biallelic GP1BB variants account for approximately 28% of genetically characterized BSS families (PMID:24934643).

Genetic studies demonstrate autosomal recessive inheritance with homozygous or compound heterozygous GP1BB variants segregating with disease in consanguineous pedigrees. A missense p.Pro74Arg mutation was confirmed homozygous in one family by microsatellite and Southern blot analyses (PMID:10928480). Multi‐family cohorts include over 59 families harboring diverse GP1BB alleles (PMID:24934643).

The variant spectrum encompasses promoter mutations (C-133G transversion reducing transcription by 84%) (PMID:8703016), missense changes (e.g., c.138G>A (p.Trp46Ter)), nonsense and frameshift alleles (e.g., c.528_550del (p.Arg177SerfsTer124)), and disulfide‐bridge disruptions (Cys5Tyr) (PMID:12958615). The Tyr88Cys variant acts dominantly in heterozygotes, causing giant platelets, and recessively in homozygotes to cause full‐blown BSS (PMID:11816714).

Functional assays in transfected cells confirm that GP1BB promoter, missense, nonsense, and frameshift mutations abrogate GPIb-IX complex assembly and surface expression (PMID:10216092; PMID:12958615). Knock-out and rescue studies further validate haploinsufficiency as the mechanism of pathogenicity (PMID:34638529).

Clinically, patients present with thrombocytopenia (HP:0001873), giant platelets (HP:0001902), prolonged bleeding time (HP:0003010), and mucocutaneous bleeding (HP:0001892). Macrothrombocytopenia in 22q11.2 deletion syndrome uncovers obligate GP1BB carrier status (PMID:38625506). Heterozygous carriers may exhibit mild thrombocytopenia and bleeding symptoms (PMID:25370924).

Integration of genetic and functional data establishes a definitive gene–disease relationship: GP1BB loss-of-function causes autosomal recessive BSS by preventing GPIb-IX complex expression. Experimental concordance across patient cells and models supports diagnosis, carrier testing, and emerging gene therapy approaches (PMID:37416759). Key Take-home: Biallelic GP1BB mutations definitively underlie BSS, guiding molecular diagnosis, family screening, and targeted management.

References

• The Journal of Biological Chemistry • 1996 • Identification of a mutation in a GATA binding site of the platelet glycoprotein Ibbeta promoter resulting in the Bernard-Soulier syndrome. PMID:8703016
• Blood • 1999 • The critical interaction of glycoprotein (GP) IBBeta with GPIX—a genetic cause of Bernard-Soulier syndrome. PMID:10216092
• Thrombosis and Haemostasis • 2000 • Homozygous Pro74→Arg mutation in the platelet glycoprotein Ibbeta gene associated with Bernard-Soulier syndrome. PMID:10928480
• Thrombosis and Haemostasis • 2003 • Disruption of the Cys5-Cys7 disulfide bridge in the platelet glycoprotein Ibbeta prevents the normal maturation and surface exposure of GPIb-IX complexes. PMID:12958615
• Thrombosis and Haemostasis • 2001 • A missense mutation (Tyr88 to Cys) in the platelet membrane glycoprotein Ibbeta gene affects GPIb/IX complex expression—Bernard-Soulier syndrome in the homozygous form and giant platelets in the heterozygous form. PMID:11816714
• Human Mutation • 2014 • Spectrum of the mutations in Bernard-Soulier syndrome. PMID:24934643
• International Journal of Molecular Sciences • 2021 • A Novel Mutation in GP1BB Reveals the Role of the Cytoplasmic Domain of GPIbβ in the Pathophysiology of Bernard-Soulier Syndrome and GPIb-IX Complex Assembly. PMID:34638529
• International Journal of Hematology • 2024 • Bernard-Soulier syndrome caused by a novel GP1BB variant and 22q11.2 deletion. PMID:38625506
• American Journal of Hematology • 2015 • Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome—a case control study. PMID:25370924
• Molecular Therapy—Nucleic Acids • 2023 • Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C. PMID:37416759

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