Enhanced hepatic clearance of hyposialylated platelets explains thrombocytopenia in GNE-related macrothrombocytopenia

Glucosamine (UDP-N-Acetyl)-2-Epimerase and N-Acetylmannosamine Kinase (GNE) is the rate-limiting enzyme in the synthesis of sialic acid. Mutations in the GNE gene are associated with adult-onset myopathy. Recently, four GNE variants were identified in patients with congenital macrothrombocytopenia. The relationship between GNE mutations and macrothrombocytopenia is incompletely understood, as most myopathy patients have normal platelet counts. Here, we investigated the molecular mechanism underlying GNE-related thrombocytopenia. We identified 2 female siblings with a severe congenital macrothrombocytopenia, a severe bleeding pattern and a homozygous p.R420Q mutation in the GNE gene. Functional characterization of the 420Q-GNE variant confirmed loss of function. Patient platelets showed hyposialylation, but plasma markers for glycosylation were normal. 111 Indium-labeled autologous platelet scanning in one patient indicated hepatic platelet sequestration and a decreased platelet half-life. Consistent with these findings, uptake of patient platelets by THP-1 macrophages and HepG2 liver cells was strongly increased. One patient was treated with romiplostim, which increased the platelet count and ameliorated the bleeding tendency. In conclusion, this study shows that the 420Q-GNE variant results in hyposialylation of glycans on platelets, which leads to rapid clearance by the liver and causes thrombocytopenia. Bleeding symptoms can be treated with romiplostim.