Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2

Meeths, Marie; Entesarian, Miriam; Al‐Herz, Waleed; Chiang, Samuel C.C.; Wood, Stephanie; Al-Ateeqi, Wafa; Almazán, Francisco; Boelens, Jaap Jan; Hasle, Henrik; Ifversen, Marianne; Lund, Bendik; M, van den Berg; Gustafsson, Britt; Hjelmqvist, Hans; Nordenskjöld, Magnus; Bryceson, Yenan T.; Henter, Jan‐Inge

doi:10.1182/blood-2010-05-282541

Cited by 113 publications

(95 citation statements)

References 53 publications

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“…The R39P mutation was identified in an FHL5 patient carrying a deleterious splice site mutation in the other allele (47). Our studies suggest that R39P Munc18-2 does not fold properly (Fig.…”

Section: Discussionmentioning

confidence: 92%

Syntaxin binding mechanism and disease-causing mutations in Munc18-2

Hackmann

Graham

Ehl³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Understanding the molecular mechanisms that control secretion from cytotoxic T lymphocytes (CTL) and natural killer (NK) cells is the key for understanding how these cells destroy virally infected and tumourigenic cells. Precisely how mutations in Munc18-2 and syntaxin 11 (Stx11) give rise to loss of CTL and NK function and severe immunodeficiency is poorly understood. In this study we present a crystal structure of human Munc18-2 and analyze the disease-causing mutations. Our findings reveal a mechanism that allows Munc18-2 to selectively bind Stx11 and identify potential surrogate binding partners, which could restore Munc18-Stx function upon IL-2 activation.

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Section: Discussionmentioning

confidence: 92%

Syntaxin binding mechanism and disease-causing mutations in Munc18-2

Hackmann

Graham

Ehl³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In these diseases, there is markedly reduced degranulation of lytic granules in cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and platelets. In addition, patients with FHL5 have been shown to suffer from gastrointestinal symptoms and bleeding disorders, possibly from disrupted degranulation from mast cells and neutrophils, as well as platelets (13). Nonetheless, the underlying mechanisms, and particularly the structural determinants of the functions of these proteins, have not been investigated in a detailed manner.…”

mentioning

confidence: 99%

Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation

Bin

Jung

Piggott

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The function of the Munc18-1 protein hydrophobic pocket, which interacts with the syntaxin-1 N-terminal peptide, has been highly controversial in neurosecretion. Recent analysis of patients with familial hemophagocytic lymphohistiocytosis type 5 has identified the E132A mutation in the hydrophobic pocket of Munc18-2, prompting us to examine the role of this region in the context of immune cell secretion. Double knockdown of Munc18-1 and Munc18-2 in RBL-2H3 mast cells eliminates both IgE-dependent and ionomycin-induced degranulation and causes a significant reduction in syntaxin-11 without altering expressions of the other syntaxin isoforms examined. These phenotypes were effectively rescued on reexpression of wild-type Munc18-1 or Munc18-2 but not the mutants (F115E, E132A, and F115E/E132A) in the hydrophobic pocket of Munc18. In addition, these mutants show that they are unable to directly interact with syntaxin-11, as tested through protein interaction experiments. Our results demonstrate the crucial roles of the hydrophobic pocket of Munc18 in mast cell degranulation, which include the regulation of syntaxin-11. We also suggest that the functional importance of this region is significantly different between neuronal and immune cell exocytosis.membrane fusion | FHL5

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“…Previous reports have documented the role of STXBP2 in natural killer (NK) cell, cell T lymphocyte, and platelet degranulation in patients with FHL-5. [2][3][4] Some of the clinical features of FHL-5, such as the increased susceptibility to gastrointestinal tract bacterial infection, 5 have remained unexplained. Therefore, it seems possible that STXBP2 plays a role in other leukocytes, such as neutrophils.…”

Section: Introductionmentioning

confidence: 99%

Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations

Zhao

Gazendam

Drewniak

et al. 2013

Blood

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Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory

Cited by 113 publications

References 53 publications

Syntaxin binding mechanism and disease-causing mutations in Munc18-2

Syntaxin binding mechanism and disease-causing mutations in Munc18-2

Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation

Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations

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