STX11 was first reported in relation to autosomal recessive familial hemophagocytic lymphohistiocytosis 4 (FHL4) in 2005 (zur Stadt U et al., 2005, PMID: 15703195). FHL is characterized by episodes of severe and overwhelming systemic immune activation which is often lethal in the absence of appropriate treatment and subsequent allogeneic hematopoietic cell transplantation (HCT). Typical features include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, elevated levels of soluble IL-2 receptor, decreased or absent NK cell function, and hemophagocytosis observed on pathologic inspection of bone marrow or other tissues. Patients with defects in syntaxin 11 result in severely compromised NK degranulation and cytotoxicity. STX11 is expressed in many tissues, but with regard to the immune system, Syntaxin 11 is necessary for normal NK cell and CD8+T cell cytotoxic granule exocytosis and has been implicated in being involved in neutrophil granule exocytosis as well. The exact molecular mechanism of STX11 is not clear. This curation includes 11 variants (including in-frame deletions, missense, nonsense, and frameshift) found in 10 probands from two publications (PMIDs: 20486178, 16582076, 24459464, 26709266, 21298754, 19967551, 31207086 and 31770233). Additional cases are available in the literature however the maximum score for genetic evidence has been reached. A role in disease is supported by increased expression of STX11 in NK cells and CD8+ T cells, as well as in NK92 cells (PMID:17525286). Functional alteration in the patient's cells also showed how a mutation resulted in a complete loss of STX11 function (PMID: 20486178). A Stx11−/− mouse model demonstrated the phenotypes associated with FHL4 and exhibited a defective degranulation and cytotoxic activity of lymphocytes in vitro, confirming the critical role of this SNARE protein in cytotoxic granule exocytosis. Recuse of the phenotype was also seen in this same mouse model (PMID:23160464). In summary, STX11 is definitively associated with autosomal recessive FHL4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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