Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation

Abstract

Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.

Platelet lifespan and mechanisms for clearance

“…There is an increasing number of inherited thrombocytopenias being identified that are caused by variants in genes affecting glycosylation and a comprehensive overview has recently been published [127]. Disorders associated with mutations in the genes GNE [128,129] and SLC35A1 [130,131] are caused by defects in the sialic acid cycle, and mutation in GALE disrupts glycosylation (providing the sites of binding of sialic acid) [132].…”