Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11
| Autor: | 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 |
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| Rok vydání: | 2009 |
| Předmět: |
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 |
| Zdroj: | The American Journal of Human Genetics. 85:482-492 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2009.09.005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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