Intrinsic defects in erythroid cells from familial hemophagocytic lymphohistiocytosis type 5 patients identify a role for STXBP2/Munc18-2 in erythropoiesis and phospholipid scrambling

Elena B Kostova, Boukje M Beuger, Martijn Veldthuis, Jutte van der Werff Ten Bosch, Ingrid Kühnle, Emile van den Akker, Timo K van den Berg, Rob van Zwieten, Robin van Bruggen

Research output: Contribution to journalArticle*Academicpeer-review

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.

Original languageEnglish
Pages (from-to)1072-1076.e2
JournalExperimental hematology
Volume43
Issue number12
DOIs
Publication statusPublished - Dec 2015

Keywords

  • Erythroblasts/metabolism
  • Erythropoiesis
  • Female
  • Humans
  • Ionomycin/pharmacology
  • Lymphohistiocytosis, Hemophagocytic/genetics
  • Male
  • Munc18 Proteins/biosynthesis
  • Mutation
  • Phosphatidylserines/genetics

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