GP1BA – Bernard-Soulier syndrome

Glycoprotein Ib alpha (GPIbα), encoded by GP1BA, is a subunit of the platelet GPIb-IX-V receptor complex mediating von Willebrand factor (VWF) binding and platelet adhesion. Bernard-Soulier syndrome (BSS) is a rare, congenital macrothrombocytopenia with mucocutaneous bleeding due to quantitative or qualitative defects of GPIbα and its partner subunits.

Autosomal recessive inheritance is typical, with homozygous or compound heterozygous GP1BA variants leading to absent or dysfunctional GPIbα. The c.1077G>A (p.Trp359Ter) nonsense variant was first identified in a BSS proband and truncated GP1BA polypeptide in four family members across three generations, cosegregating with disease or carrier phenotypes (PMID:2308962).

A global consortium genotyped 211 BSS families, reporting 112 distinct GP1BA variants in over 250 affected individuals, including missense, nonsense, frameshift, splice, and promoter mutations, with multiple recurrent and founder alleles across diverse populations (PMID:24934643). Segregation analysis and absence of GPIbα surface expression confirm AR inheritance.

Functional assays in CHO or 293T cells demonstrated that frameshift and nonsense GP1BA alleles fail to anchor or properly fold GPIbα, abrogating VWF binding (e.g., Trp207Gly; PMID:17083647). Charged-to-alanine scanning mutagenesis identified key VWF-binding residues Glu128 and Asp175 within the leucine-rich repeats (PMID:14757772). In vivo, zebrafish gp1ba mutants recapitulate macrothrombocytopenia, prolonged bleeding, and impaired ristocetin-induced agglutination, supporting LOF as the mechanism (PMID:35802508).

No studies have refuted the GP1BA–BSS association or identified alternative etiologies for classical AR BSS. Monoallelic GP1BA variants may cause a milder, AD macrothrombocytopenia but remain distinct from AR BSS.

In summary, there is definitive clinical validity for GP1BA as the causative gene for autosomal recessive Bernard-Soulier syndrome. Genetic testing for GP1BA variants informs diagnosis, genetic counseling, and management of BSS patients.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1990 • Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome. PMID:2308962
• Human Mutation • 2014 • Spectrum of the mutations in Bernard-Soulier syndrome. PMID:24934643
• The Journal of Biological Chemistry • 2004 • Identification of the amino acid residues of the platelet glycoprotein Ib (GPIb) essential for the von Willebrand factor binding by clustered charged-to-alanine scanning mutagenesis. PMID:14757772
• Journal of Thrombosis and Haemostasis • 2007 • Trp207Gly in platelet glycoprotein Ibalpha is a novel mutation that disrupts the connection between the leucine-rich repeat domain and the disulfide loop structure and causes Bernard-Soulier syndrome. PMID:17083647
• Blood Coagulation & Fibrinolysis • 2022 • Characterization of zebrafish gp1ba mutant and modelling Bernard-Soulier syndrome. PMID:35802508

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