Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells
Marjorie Côte, … , Alain Fischer, Geneviève de Saint Basile
Marjorie Côte, … , Alain Fischer, Geneviève de Saint Basile
Published November 2, 2009
Citation Information: J Clin Invest. 2009;119(12):3765-3773. https://doi.org/10.1172/JCI40732.
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Research Article Immunology

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.

Authors

Marjorie Côte, Mickaël M. Ménager, Agathe Burgess, Nizar Mahlaoui, Capucine Picard, Catherine Schaffner, Fahad Al-Manjomi, Musa Al-Harbi, Abdullah Alangari, Françoise Le Deist, Andrew R. Gennery, Nathalie Prince, Astrid Cariou, Patrick Nitschke, Ulrich Blank, Gehad El-Ghazali, Gaël Ménasché, Sylvain Latour, Alain Fischer, Geneviève de Saint Basile

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Figure 3

Model structure of STXBP2.

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Model structure of STXBP2. (A) A ribbon representation of the STXBP2 pro...
(A) A ribbon representation of the STXBP2 protein. By homology with STXBP1, the 3 domains are colored as follows: domain 1 in blue, domain 2 in green (with light and dark green indicating the 2 non-contiguous segments of the polypeptide chain that form this domain), domain 3a in yellow, and domain 3b in brown. The central cavity (formed by domains 1 and 3a) provides the binding surface for syntaxin. The mutated proline (P477L) and the α helix affected by the splice are highlighted in red. The IVS14-1G>C mutant induces aa replacements in the hydrophobic core. (B) Splice mutation, which replaces 17 aa of the WT sequence with 19 new residues. A remarkable conservation of a hydrophobic aa pattern can be observed. Hydrophobic aa are highlighted in green; the alternation of hydrophobic and hydrophilic aa every 3–4 residues is typical for amphipathic α helices.