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

Serena Barozzi, Valeria Bozzi, Daniela De Rocco, Tania Giangregorio, Patrizia Noris, Anna Savoia, Alessandro Pecci

Research output: Contribution to journalArticlepeer-review

Abstract

Bernard‐Soulier syndrome (BSS) is an autosomal‐recessive bleeding disorder caused by biallelic variants in the GP1BA, GP1BB, and GP9 genes encoding the subunits GPIbα, GPIbβ, and GPIX of the GPIb‐IX complex. Pathogenic variants usually affect the extracellular or transmembrane domains of the receptor subunits. We investigated a family with BSS caused by the homozygous c.528_550del (p.Arg177Serfs*124) variant in GP1BB, which is the first mutation ever identified that affects the cytoplasmic domain of GPIbβ. The loss of the intracytoplasmic tail of GPIbβ results in a mild form of BSS, characterized by only a moderate reduction of the GPIb‐IX complex expression and mild or absent bleeding tendency. The variant induces a decrease of the total platelet expression of GPIbβ; however, all of the mutant subunit expressed in platelets is correctly assembled into the GPIb‐IX complex in the plasma membrane, indicating that the cytoplasmic domain of GPIbβ is not involved in assembly and trafficking of the GPIb‐IX receptor. Finally, the c.528_550del mutation exerts a dominant effect and causes mild macrothrombocytopenia in heterozygous individuals, as also demonstrated by the investigation of a second unrelated pedigree. The study of this novel GP1BB variant provides new information on pathophysiology of BSS and the assembly mechanisms of the GPIb‐IX receptor.

Original languageEnglish
Article number10190
JournalInternational Journal of Molecular Sciences
Volume22
Issue number19
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Bernard‐Soulier syndrome
  • GPIb‐IX complex
  • Inherited platelet disorders
  • Inherited thrombocytopenia
  • VWF recep-tor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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