Novel Mutation in Syntaxin-Binding Protein 2 (STXBP2) in Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Prevents IL-2-induced Natural Killer Cell Cytotoxicity and Degranulation

Abstract

RATIONALE: Familial Hemophagocytic Lymphohistiocytosis (FHL) is an autosomal recessive primary immunodeficiency characterized by multisystem inflammation after infection. In a subset of patients (FHL-5) disease results from mutation of Munc18-2, which encodes for syntaxin-binding protein 2 (STXBP2). STXBP2 interacts with syntaxin 11, a SNARE protein, and controls vesicle fusion with the plasma membrane. In these patients, natural killer (NK) cell degranulation and cytotoxicity is impaired, but can be restored after IL-2 stimulation, suggesting an STXBP2-independent pathway to access SNARE function.