title: 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.affiliation: INSERM U768, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Côte
authors.forename: Mickaël M
authors.initials: MM
authors.lastname: Ménager
authors.forename: Agathe
authors.initials: A
authors.lastname: Burgess
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaffner
authors.forename: Fahad
authors.initials: F
authors.lastname: Al-Manjomi
authors.forename: Musa
authors.initials: M
authors.lastname: Al-Harbi
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alangari
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
authors.forename: Nathalie
authors.initials: N
authors.lastname: Prince
authors.forename: Astrid
authors.initials: A
authors.lastname: Cariou
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Ulrich
authors.initials: U
authors.lastname: Blank
authors.forename: Gehad
authors.initials: G
authors.lastname: El-Ghazali
authors.forename: Gaël
authors.initials: G
authors.lastname: Ménasché
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D005089:Exocytosis / Q000235:genetics / Q000502:physiology; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D007438:Introns; D007694:Killer Cells, Natural / Q000502:physiology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000145:classification / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051938:Munc18 Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D010375:Pedigree; D050765:Qa-SNARE Proteins / Q000502:physiology; D022821:RNA Splice Sites; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; D022821:RNA Splice Sites; C541732:STX11 protein, human; C497940:STXBP2 protein, human