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

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.

DOI: 10.1172/JCI40732

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@article{Cte2009Munc182DC, title={Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.}, author={Marjorie C{\^o}te and Micka{\"{e}l M. M{\'e}nager and Agathe Burgess and Nizar Mahlaoui and Capucine Picard and Catherine Schaffner and Fahad Al-Manjomi and Musa Al-Harbi and Abdullah A Alangari and Françoise le Deist and Andrew Gennery and Nathalie Prince and Astrid Cariou and Patrick Linsel Nitschke and Ulrich Blank and Gehad El-Ghazali and Ga{\"{e}l M{\'e}nasch{\'e} and Sylvain Latour and Alain Fischer and Genevi{\`e}ve de Saint Basile}, journal={The Journal of clinical investigation}, year={2009}, volume={119 12}, pages={3765-73} }