GP9 – Bernard-Soulier syndrome

Bernard-Soulier syndrome (BSS; Bernard-Soulier syndrome) is a rare autosomal recessive bleeding disorder characterized by macrothrombocytopenia (HP:0001873) and giant platelets (HP:0001902). BSS results from defective assembly of the platelet GPIb-IX-V receptor complex, critical for von Willebrand factor–mediated adhesion, due to biallelic GP9 variants.

Extensive genetic evidence supports a definitive association between GP9 and BSS. Over 40 probands from more than 15 unrelated families harbor homozygous or compound heterozygous GP9 variants, with consistent segregation and absence of the same mutations in healthy controls (PMID:24934643). Pedigree analyses include a Swiss kindred with four affected members (PMID:19404517) and five Finnish families encompassing 11 patients homozygous for c.182A>G (p.Asn61Ser) (PMID:10227459).

The GP9 variant spectrum comprises predominantly missense substitutions within the conserved leucine-rich motif (e.g., c.182A>G (p.Asn61Ser)), along with frameshift and nonsense alleles that truncate the transmembrane or cytoplasmic domains. To date, at least 20 distinct missense and 8 loss-of-function variants have been reported across diverse populations.

Segregation studies identified 19 additional affected relatives carrying biallelic GP9 variants, confirming autosomal recessive inheritance and co-segregation of genotype with phenotype (PMID:10227459; PMID:19404517).

Functional assays in CHO cells demonstrate that GP9 mutants such as Asp21Gly and Asn45Ser fail to reach the cell surface and cannot support GPIb-IX receptor expression, indicating a biosynthetic assembly defect (PMID:8608225). A CRISPR-Cas9–generated zebrafish gp9 knockout recapitulates thrombocytopenia and bleeding diathesis, validating the pathogenic mechanism in vivo (PMID:34407604).

Mechanistically, GP9 pathogenic alleles lead to loss of membrane anchoring and disruption of the GPIb-IX-V complex, resulting in absent or severely reduced platelet adhesion under shear. There is no contradictory evidence disputing this association.

Key take-home: GP9 sequencing should be included in diagnostic panels for autosomal recessive thrombocytopenia. Identification of biallelic GP9 variants enables definitive diagnosis, informed genetic counseling, and future exploration of gene therapy for BSS type C.

References

• Human Mutation • 2014 • Spectrum of the mutations in Bernard-Soulier syndrome PMID:24934643
• Hamostaseologie • 2009 • A large Swiss family with Bernard-Soulier syndrome - Correlation phenotype and genotype PMID:19404517
• European Journal of Haematology • 1999 • Variant Bernard-Soulier syndrome due to homozygous Asn45Ser mutation in the platelet glycoprotein (GP) IX in seven patients of five unrelated Finnish families PMID:10227459
• Blood • 1996 • Biosynthetic defect in platelet glycoprotein IX mutants associated with Bernard-Soulier syndrome PMID:8608225
• Haematologica • 2022 • Establishment of a Bernard-Soulier syndrome model in zebrafish PMID:34407604

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