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

Udo Zur Stadt, Jan Rohr, Wenke Seifert, Florian Koch, Samantha Grieve, Julia Pagel, Julia Strauss, Brigitte Kasper, Gudrun Nürnberg, Christian Becker, Andrea Maul-Pavicic, Karin Beutel, Gritta Janka, Gillian M. Griffiths, Stephan Ehl, Hans Christian Hennies

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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.

Original languageEnglish
Pages (from-to)482-492
Number of pages11
JournalAmerican Journal of Human Genetics
Volume85
Issue number4
DOIs
Publication statusPublished - 9 Oct 2009
Externally publishedYes

Fingerprint

Qa-SNARE Proteins
Hemophagocytic Lymphohistiocytosis
Mutation
Munc18 Proteins
Immunological Synapses
SNARE Proteins
Transport Vesicles
Natural Killer T-Cells
Saudi Arabia
Protein Stability
Exocytosis
Missense Mutation
Turkey
Single Nucleotide Polymorphism
Chromosomes
Cell Membrane
Lymphocytes
Phenotype
Hemophagocytic Lymphohistiocytosis, Familial, 5
Proteins

Cite this

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 M. ; Ehl, Stephan ; Hennies, Hans Christian. / Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. In: American Journal of Human Genetics. 2009 ; Vol. 85, No. 4. pp. 482-492.
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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.",
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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, GM, 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', American Journal of Human Genetics, vol. 85, no. 4, pp. 482-492. https://doi.org/10.1016/j.ajhg.2009.09.005

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 M.; Ehl, Stephan; Hennies, Hans Christian.

In: American Journal of Human Genetics, Vol. 85, No. 4, 09.10.2009, p. 482-492.

Research output: Contribution to journalArticle

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 M.

AU - Ehl, Stephan

AU - Hennies, Hans Christian

PY - 2009/10/9

Y1 - 2009/10/9

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

KW - Male

KW - Munc18 Proteins

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Qa-SNARE Proteins

KW - SNARE Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.ajhg.2009.09.005

DO - 10.1016/j.ajhg.2009.09.005

M3 - Article

VL - 85

SP - 482

EP - 492

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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ER -