ArticleBlood2015
Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion.
Article in Blood, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 124 citations in OpenAlex.
- Trial
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- Role of DOCK8 in cytokine storm syndromes.The Journal of allergy and clinical immunology · 2025Article
- Clinical and genetic analysis of macrophage activation syndrome complicating juvenile idiopathic inflammatory myopathies.Pediatric research · 2025Article
- Neonatal-onset familial hemophagocytic lymphohistiocytosis: a case report with genetic confirmation of PRF1 mutations.Frontiers in genetics · 2025Article
- Breaking Down Barriers: Epithelial Contributors to Monogenic IBD Pathogenesis.Inflammatory bowel diseases · 2024Review
- Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes.Nature communications · 2024Article
- Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
- Salvage Therapy and Allogeneic Hematopoietic Cell Transplantation for the Severe Cytokine Storm Syndrome of Hemophagocytic Lymphohistiocytosis.Advances in experimental medicine and biology · 2024Review
- Etoposide Therapy of Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- IL-1 Family Blockade in Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Murine Models of Secondary Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Murine Models of Familial Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Bacteria-Associated Cytokine Storm Syndrome.Advances in experimental medicine and biology · 2024Review
- CD8Advances in experimental medicine and biology · 2024Review
- Immunology of Cytokine Storm Syndromes: Natural Killer Cells.Advances in experimental medicine and biology · 2024Review
- Laboratory Features and Pathology of Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- History of Hemophagocytic Lymphohistiocytosis.Advances in experimental medicine and biology · 2024Review
- A Case Report of Pregnancy Complicated with Primary Hemophagocytic Lymphohistiocytosis.International journal of women's health · 2024Article
- Extended-Synaptotagmin-1 and -2 control T cell signaling and function.EMBO reports · 2024Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
Abstract
Familial hemophagocytic lymphohistiocytosis (F-HLH) and Griscelli syndrome type 2 (GS) are life-threatening immunodeficiencies characterized by impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell lytic activity. In the majority of cases, these disorders are caused by biallelic inactivating germline mutations in genes such as RAB27A (GS) and PRF1, UNC13D, STX11, and STXBP2 (F-HLH). Although monoallelic (ie, heterozygous) mutations have been identified in certain patients, the clinical significance and molecular mechanisms by which these mutations influence CTL and NK cell function remain poorly understood. Here, we characterize 2 novel monoallelic hemophagocytic lymphohistiocytosis (HLH)-associated mutations affecting codon 65 of STXPB2, the gene encoding Munc18-2, a member of the SEC/MUNC18 family. Unlike previously described Munc18-2 mutants, Munc18-2(R65Q) and Munc18-2(R65W) retain the ability to interact with and stabilize syntaxin 11. However, presence of Munc18-2(R65Q/W) in patient-derived lymphocytes and forced expression in control CTLs and NK cells diminishes degranulation and cytotoxic activity. Mechanistic studies reveal that mutations affecting R65 hinder membrane fusion in vitro by arresting the late steps of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly. Collectively, these results reveal a direct role for SEC/MUNC18 proteins in promoting SNARE-complex assembly in vivo and suggest that STXBP2 R65 mutations operate in a novel dominant-negative fashion to impair lytic granule fusion and contribute to HLH.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.