Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.

Content Provider	Semantic Scholar
Author	Côte, Marjorie Ménager, Mickaël M. Burgess, Agathe Mahlaoui, Nizar Picard, Capucine Schaffner, Catherine Al-Manjomi, Fahad Al-Harbi, Musa Alangari, Abdullah A. Deist, Françoise Le Gennery, Andrew R. Prince, Nathalie Cariou, Astrid Nitschke, Patrick Blank, Ulrich El-Ghazali, Gehad Menasche, Gaël Latour, Sylvain Fischer, Alain Basile, Geneviève De Saint
Copyright Year	2009
Abstract	Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as "FHL5"). Lymphoblasts isolated from these patients had strongly decreased STXBP2 protein expression, and NK cells exhibited impaired cytotoxic granule exocytosis, a defect that could be overcome by ectopic expression of wild-type STXBP2. Furthermore, we provide evidence that syntaxin-11 is the main partner of STXBP2 in lymphocytes, as its expression required the presence of STXBP2. Our work shows that STXBP2 deficiency causes FHL5. These data indicate that STXBP2 is required at a late step of the secretory pathway for the release of cytotoxic granules by binding syntaxin 11, another component of the intracellular membrane fusion machinery.
Starting Page	355
Ending Page	360
Page Count	6
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://fac.ksu.edu.sa/sites/default/files/familial_hlh.pdf
PubMed reference number	19884660v1
Alternate Webpage(s)	https://doi.org/10.1172/JCI40732
DOI	10.1172/jci40732
Journal	The Journal of clinical investigation
Volume Number	119
Issue Number	12
Language	English
Access Restriction	Open
Subject Keyword	Autosomal recessive inheritance Cell secretion Classical galactosemia Ectopic Gene Expression Exocytosis Familial Hemophagocytic Lymphocytosis Genetic Heterogeneity Granule HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 3 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5 Hemophagocytic lymphohistiocytosis, familial, 4 Hyperlipoproteinemia Type I Immune System Diseases Infiltration Intracellular Membranes Lymphoblast count Lymphohistiocytosis, Hemophagocytic Membrane Fusion Mutation Organ PRF1 gene Patients Qa-SNARE Proteins STX11 gene STX11 protein, human STXBP2 gene Secretory Pathway Subgroup UNC13D gene
Content Type	Text
Resource Type	Article