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, Jahrgang 85, Nr. 4, 10.2009, S. 482-492.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -