STX11 Mutations and Clinical Phenotypes of Familial Hemophagocytic Lymphohistiocytosis in North America

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 07/2010; 55(1):134-40. DOI: 10.1002/pbc.22499
Source: PubMed


Mutations in STX11 are responsible for Familial Hemophagocytic Lymphohistiocytosis (FHLH) type 4, a rare primary immunodeficiency which has previously been observed only in patients of Kurdish, Turkish, and Lebanese ethnic background.
We reviewed our experience with STX11 mutations among North American patients and studied the impact of patient mutations upon syntaxin 11 expression and NK cell function.
Between 2007 and 2008, 243 patients with HLH (lacking disease-causing mutations in PRF1 and UNC13D) were referred for STX11 mutational analysis. We observed 1 novel homozygous nonsense mutation, 73 G > T (E25X), occurring in Hispanic siblings, and 2 novel biallelic heterozygous missense mutations, 106G > C (E36Q) and 616G > A (E206K), occurring in 1 Caucasian patient. The N-terminal nonsense mutation resulted in absence of detectable syntaxin 11 and abrogation of in vitro NK cell degranulation and function, while the biallelic heterozygous missense mutations resulted in detectable mutated syntaxin 11 and preservation of in vitro NK cell degranulation and cytotoxicity. The two sibling patients with the nonsense mutations presented with HLH during infancy, whereas the patient with biallelic heterozygous missense mutations presented at 5 years of age.
We conclude that mutations in STX11 are responsible for HLH in approximately 1% of North American patients and can cause variable defects in syntaxin 11 expression and function with resultant impact on clinical phenotype.

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Available from: Kejian Zhang, Aug 26, 2015
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    • "Herein we dissect the molecular basis for FHL-4 by examining how disease-associated mutations affect the interaction of syntaxin 11 with other proteins and cellular membranes. FHL-4 deletion and frameshift mutations result in the abrogation of secretory lysosome exocytosis and the consequent loss of NK cell cytotoxicity [7]–[11]. We show that these FHL-4 mutations have differential effects on SNARE binding by syntaxin 11, but the FHL-4 mutant proteins retain a Munc18-2 binding site. "
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    ABSTRACT: Natural killer (NK) cell secretory lysosome exocytosis and cytotoxicity are impaired in familial hemophagocytic lymphohistiocytosis type 4 (FHL-4), a disorder caused by mutations in the gene encoding the SNARE protein syntaxin 11. We show that syntaxin 11 binds to SNAP23 in NK cells and that this interaction is reduced by FHL-4 truncation and frameshift mutation proteins that delete all or part of the SNARE domain of syntaxin 11. In contrast the FHL-4 mutant proteins bound to the Sec-1/Munc18-like (SM) protein Munc18-2. We demonstrate that the C-terminal cysteine rich region of syntaxin 11, which is deleted in the FHL-4 mutants, is S-acylated. This posttranslational modification is required for the membrane association of syntaxin 11 and for its polarization to the immunological synapse in NK cells conjugated to target cells. Moreover, we show that Munc18-2 is recruited by syntaxin 11 to intracellular membranes in resting NK cells and to the immunological synapse in activated NK cells. This recruitment of Munc18-2 is abolished by deletion of the C-terminal cysteine rich region of syntaxin 11. These results suggest a pivotal role for S-acylation in the function of syntaxin 11 in NK cells.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Therefore, the consequence of mutations in PRF1 gene is inhibition of cytotoxicity. Results of the functional tests reveal low cytotoxic activity but normal degranulation (Marsh et al. 2010a "
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    ABSTRACT: Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a heterogenic syndrome, which leads to an acute, life-threatening inflammatory reaction. HLH occurs both in children and adults, and can be triggered by various inherited as well as acquired factors. Depending on the etiology, HLH can be divided into genetic (i.e., primary) and acquired (i.e., secondary) forms. Among genetic HLH forms, one can distinguish between familial HLH and other genetically conditioned forms of HLH. Acquired HLH can be typically triggered by infections, autoimmune diseases, and malignancies. The most common symptoms of HLH are unremitting fever, splenomegaly, and peripheral blood cytopenia. Some severely ill patients present with central nervous system involvement. Laboratory tests reveal hyperferritinemia (often >10,000 μg/L), increased serum concentration of soluble receptor α for interleukin-2 (>2,400 U/L), hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hyponatremia, hypoproteinemia, and elevated liver transaminases and bilirubin. Prognosis in HLH is very serious. Genetic HLH is always lethal if adequate therapy is not administered. Similarly, severe acquired cases often lead to death without appropriate treatment. Since HLH can be encountered by various specialists in the medical field, basic knowledge of this entity such as diagnostic criteria and treatment should be familiar to all physicians.
    Full-text · Article · Feb 2014 · Archivum Immunologiae et Therapiae Experimentalis
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    ABSTRACT: Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed. We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2. All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal. Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.
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