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Niemann-Pick type C is a lysosomal storage disease associated with mutations in NPC1 or NPC2, resulting in an accumulation of cholesterol in the endosomal-lysosomal system. Niemann-Pick type C has a clinical spectrum that ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease combined with remarkably, in some cases, hematological defects such as thrombocytopenia, anemia and petechial rash. A role of NPC1 in hematopoiesis was never shown. Here, we describe platelet function abnormalities in three unrelated patients with a proven genetic and biochemical NPC1 defect. Their platelets have reduced aggregations, P-selectin expression and ATP secretions that are compatible with the observed abnormal alpha and reduced dense granules as studied by electron microscopy and CD63 staining after platelet spreading. Their blood counts were normal. NPC1 expression was shown in platelets and megakaryocytes (MKs). In vitro differentiated MKs from NPC1 patients exhibit hyperproliferation of immature MKs with different CD63(+) granules and abnormal cellular accumulation of cholesterol as shown by filipin stainings. The role of NPC1 in megakaryopoiesis was further studied using zebrafish with GFP-labeled thrombocytes or DsRed-labeled erythrocytes. NPC1 depletion in zebrafish resulted in increased cell death in the brain and abnormal cellular accumulation of filipin. NPC1-depleted embryos presented with thrombocytopenia and mild anemia as studied by flow cytometry and real-time QPCR for specific blood cell markers. In conclusion, this is the first report, showing a role of NPC1 in platelet function and formation but further studies are needed to define how cholesterol storage interferes with these processes.

NPC1 defect results in abnormal platelet formation and function: studies in Niemann–Pick disease type C1 patients and zebrafish