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Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11

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Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. / zur Stadt, Udo; Rohr, Jan; Seifert, Wenke; Koch, Florian; Grieve, Samantha; Pagel, Julia; Strauss, Julia; Kasper, Brigitte; Nürnberg, Gudrun; Becker, Christian; Maul-Pavicic, Andrea; Beutel, Karin; Janka, Gritta; Griffiths, Gillian; Ehl, Stephan; Hennies, Hans Christian.

In: AM J HUM GENET, Vol. 85, No. 4, 10.2009, p. 482-492.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

zur Stadt, U, Rohr, J, Seifert, W, Koch, F, Grieve, S, Pagel, J, Strauss, J, Kasper, B, Nürnberg, G, Becker, C, Maul-Pavicic, A, Beutel, K, Janka, G, Griffiths, G, Ehl, S & Hennies, HC 2009, 'Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11', AM J HUM GENET, vol. 85, no. 4, pp. 482-492. https://doi.org/10.1016/j.ajhg.2009.09.005

APA

zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nürnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., & Hennies, H. C. (2009). Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. AM J HUM GENET, 85(4), 482-492. https://doi.org/10.1016/j.ajhg.2009.09.005

Vancouver

zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. AM J HUM GENET. 2009 Oct;85(4):482-492. https://doi.org/10.1016/j.ajhg.2009.09.005

Bibtex

@article{44d8a76145ed4fa2a0ea3c624fa0ac4b,
title = "Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11",
abstract = "Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.",
keywords = "Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 19, Exocytosis, Female, Genotype, Humans, Infant, Lymphohistiocytosis, Hemophagocytic/genetics, Male, Munc18 Proteins/genetics, Mutation, Polymorphism, Single Nucleotide, Qa-SNARE Proteins/genetics, SNARE Proteins/metabolism",
author = "{zur Stadt}, Udo and Jan Rohr and Wenke Seifert and Florian Koch and Samantha Grieve and Julia Pagel and Julia Strauss and Brigitte Kasper and Gudrun N{\"u}rnberg and Christian Becker and Andrea Maul-Pavicic and Karin Beutel and Gritta Janka and Gillian Griffiths and Stephan Ehl and Hennies, {Hans Christian}",
year = "2009",
month = oct,
doi = "10.1016/j.ajhg.2009.09.005",
language = "English",
volume = "85",
pages = "482--492",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11

AU - zur Stadt, Udo

AU - Rohr, Jan

AU - Seifert, Wenke

AU - Koch, Florian

AU - Grieve, Samantha

AU - Pagel, Julia

AU - Strauss, Julia

AU - Kasper, Brigitte

AU - Nürnberg, Gudrun

AU - Becker, Christian

AU - Maul-Pavicic, Andrea

AU - Beutel, Karin

AU - Janka, Gritta

AU - Griffiths, Gillian

AU - Ehl, Stephan

AU - Hennies, Hans Christian

PY - 2009/10

Y1 - 2009/10

N2 - Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.

AB - Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.

KW - Child, Preschool

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 19

KW - Exocytosis

KW - Female

KW - Genotype

KW - Humans

KW - Infant

KW - Lymphohistiocytosis, Hemophagocytic/genetics

KW - Male

KW - Munc18 Proteins/genetics

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Qa-SNARE Proteins/genetics

KW - SNARE Proteins/metabolism

U2 - 10.1016/j.ajhg.2009.09.005

DO - 10.1016/j.ajhg.2009.09.005

M3 - SCORING: Journal article

C2 - 19804848

VL - 85

SP - 482

EP - 492

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 4

ER -