Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.
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.
Côte
Marjorie
M
INSERM U768, Hôpital Necker-Enfants Malades, Paris, France.
Ménager
Mickaël M
MM
Burgess
Agathe
A
Mahlaoui
Nizar
N
Picard
Capucine
C
Schaffner
Catherine
C
Al-Manjomi
Fahad
F
Al-Harbi
Musa
M
Alangari
Abdullah
A
Le Deist
Françoise
F
Gennery
Andrew R
AR
Prince
Nathalie
N
Cariou
Astrid
A
Nitschke
Patrick
P
Blank
Ulrich
U
El-Ghazali
Gehad
G
Ménasché
Gaël
G
Latour
Sylvain
S
Fischer
Alain
A
de Saint Basile
Geneviève
G
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
D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; D022821:RNA Splice Sites; C541732:STX11 protein, human; C497940:STXBP2 protein, human