Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver

Abstract

Sialic acid is a common terminal residue of glycans on proteins and acidic sphingolipids such as gangliosides with important biological functions. The sialylation process is controlled by more than 20 different sialyltransferases, many of which exhibit overlapping functions. Thus, it is difficult to determine the overall biological function of sialylation by targeted deletion of individual sialyltransferase. To address this question, we established a mouse line with the Slc35a1 gene flanked by loxP sites. Slc35a1 encodes the CMP-sialic acid transporter that transports CMP-sialic acid from cytoplasm into the Golgi apparatus for sialylation. Here we report our study regarding the role of sialylation on megakaryocytes and platelets using a mouse line with significantly reduced sialylation in megakaryocytes and platelets (Plt Slc35a1-/-). The major phenotype of Plt Slc35a1-/- mice was thrombocytopenia. The number of bone marrow megakaryocytes in Plt Slc35a1-/- mice was reduced, and megakaryocyte maturation was also impaired. In addition, an increased number of desialylated platelets was cleared by Kupffer cells in the liver of Plt Slc35a1-/- mice. This study provides new insights into the role of sialylation in platelet homeostasis and the mechanisms of thrombocytopenia in diseases associated with platelet desialylation, such as immune thrombocytopenic purpura and a rare congenital disorder of glycosylation (CDG), SLC35A1-CDG, which is caused by SLC35A1 mutations.

The promiscuous binding pocket of SLC35A1 ensures redundant transport of CDP-ribitol to the Golgi

“…Mutations in SLC35A1 in humans lead to intellectual disability and bleeding diathesis ( 25 , 26 , 27 ). Platelet-specific inactivation of SLC35A1 in mice led to reduced platelet counts ( 28 ). Cells from affected patients show a deficiency in sialylation and CMP-sialic acid uptake into the Golgi apparatus ( 26 ).…”

Platelet desialylation and TFH cells–the novel pathway of immune thrombocytopenia

“…Moreover, the loss of sialic acid residues on the platelet surface is associated with a reduction in the lymphocyte Treg subset, and it has been reported that sialylated antigens can inhibit the generation and function of T cells by regulating dendritic cells [ 77 ], which suggests a potential correlation between platelet desialylation and the immune response [ 78 ]. It has also been shown that Slc35a1 mutations are closely related to the progression of ITP via platelet desialylation [ 79 ].…”

“…Some studies have provided direct evidence that neuraminidase will induce the desialylation of platelet-derived growth factor (PDGF) receptors via the mitogenic ligand PDGF-BB and thus diminish intracellular signals [ 83 ]. Moreover, studies have proven that Slc35a1 mutations significantly reduced sialylation in megakaryocytes, thus affecting the number and maturation of megakaryocytes from BM [ 79 ]. A recent study has also proven that autoantibodies can induce the cleavage of silica acid from not only platelets but also megakaryocytes, and desialylation can lead to impaired platelet adhesion and megakaryocyte differentiation.…”

Platelets and Defective N-Glycosylation

“…Evidence was found for a very short platelet life span as well [120][121][122]. A mouse model lacking specifically Slc35a1 in megakaryocytes showed thrombocytopenia, decreased megakaryocyte maturation, and increased platelet clearance [123].…”