title: Intrinsic defects in erythroid cells from familial hemophagocytic lymphohistiocytosis type 5 patients identify a role for STXBP2/Munc18-2 in erythropoiesis and phospholipid scrambling.
abstract: Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is a rare genetic disorder caused by mutations in STXBP2/Munc18-2. Munc18-2 plays a role in the degranulation machinery of natural killer cells and cytotoxic T lymphocytes. Mutations in STXBP2/Munc18-2 lead to impaired killing of target cells by natural killer cells and cytotoxic T lymphocytes, which in turn results in elevated levels of the inflammatory cytokine interferon γ, macrophage activation, and hemophagocytosis. Even though patients with FHL-5 present with anemia and hemolysis, no link between the disease and the erythroid lineage has been established. Here we report that red blood cells express Munc18-2 and that erythroid cells from patients with FHL-5 exhibit intrinsic defects caused by STXBP2/Munc18-2 mutations. Red blood cells from patients with FHL-5 expose less phosphatidylserine on their surface upon Ca(2+) ionophore ionomycin treatment. Furthermore, cultured erythroblasts from patients with FHL-5 display defective erythropoiesis characterized by decreased CD235a expression and aberrant cell morphology.
authors: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands.
authors: Elena B
authors: EB
authors: Kostova
authors: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands.
authors: Boukje M
authors: BM
authors: Beuger
authors: Laboratory for Red Blood Cell Diagnostics, Sanquin, Amsterdam, The Netherlands.
authors: Martijn
authors: M
authors: Veldthuis
authors: Department of Pediatrics, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors: Jutte
authors: J
authors: van der Werff Ten Bosch
authors: Department of Pediatrics, University Medicine Göttingen, Göttingen, Germany.
authors: Ingrid
authors: I
authors: Kühnle
authors: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.
authors: Emile
authors: E
authors: van den Akker
authors: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands.
authors: Timo K
authors: TK
authors: van den Berg
authors: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Red Blood Cell Diagnostics, Sanquin, Amsterdam, The Netherlands.
authors: Rob
authors: R
authors: van Zwieten
authors: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: r.vanbruggen@sanquin.nl.
authors: Robin
authors: R
authors: van Bruggen
mesh_terms: D004900:Erythroblasts / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis; D005260:Female; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051938:Munc18 Proteins / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D010718:Phosphatidylserines / Q000235:genetics / Q000378:metabolism*
chemical_list: D051938:Munc18 Proteins; D010718:Phosphatidylserines; C497940:STXBP2 protein, human; D015759:Ionomycin