Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11
العنوان: | Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11 |
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المؤلفون: | Brigitte Kasper, Udo zur Stadt, Florian Koch, Gudrun Nürnberg, Gritta Janka, Julia Pagel, Christian Becker, Wenke Seifert, Samantha Grieve, Stephan Ehl, Karin Beutel, Andrea Maul-Pavicic, Jan Rohr, Hans Christian Hennies, Julia Strauß, Gillian M. Griffiths |
المصدر: | The American Journal of Human Genetics. 85:482-492 |
بيانات النشر: | Elsevier BV, 2009. |
سنة النشر: | 2009 |
مصطلحات موضوعية: | Male, Genotype, Syntaxin binding protein 2, Biology, Polymorphism, Single Nucleotide, Exocytosis, Lymphohistiocytosis, Hemophagocytic, Article, Munc18 Proteins, Genetics, medicine, Humans, Syntaxin, Missense mutation, Genetics(clinical), UNC13D, Genetics (clinical), Hemophagocytic lymphohistiocytosis, Qa-SNARE Proteins, Degranulation, Chromosome Mapping, Infant, Familial Hemophagocytic Lymphohistiocytosis, medicine.disease, Molecular biology, STX11, Child, Preschool, Mutation, Female, SNARE Proteins, Chromosomes, Human, Pair 19 |
الوصف: | 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. |
تدمد: | 0002-9297 |
الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6feb5400b7d99301a55424f7eae64765Test https://doi.org/10.1016/j.ajhg.2009.09.005Test |
حقوق: | OPEN |
رقم الانضمام: | edsair.doi.dedup.....6feb5400b7d99301a55424f7eae64765 |
قاعدة البيانات: | OpenAIRE |
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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. 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