Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

STXBP2 Deficiency

Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_203-1


STXBP2 is located at 19p13 and encodes Munc18-2, a 19-exon, 593 amino acid, 66 kDa protein that is highly expressed in hematopoietic cells (Côte et al. 2009; zur Stadt et al. 2009).

Molecular Function

Cytotoxic T cells and NK cells kill target cells by mobilizing secretory granules containing perforin and other agents, such as granzyme, to the cellular membrane and releasing the contents into the intercellular space at the immunologic synapse. Toward the final steps of the degranulation pathway, lytic granules are tethered to the plasma membrane through interactions between Rab27a and Munc13-4. Syntaxin-11 and Munc18-2 then work cooperatively to enable lytic granule secretion. During degranulation, syntaxin-11 localizes to the plasma membrane at immunologic synapses to promote docking of lytic granules. This initial syntaxin-11 plasma membrane localization requires Munc18-2 (Dieckmann et al. 2015). In human cytotoxic T cells, syntaxin-11 then complexes with SNAP23 and...

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  1. Bezdjian A, Bruijnzeel H, Pagel J, Daniel SJ, Thomeer HGXM. Low-frequency sensorineural hearing loss in familial hemophagocytic lymphohistiocytosis type 5. Ann Otol Rhinol Laryngol. 2018;127:409–13.CrossRefGoogle Scholar
  2. Brochetta C, Vita F, Tiwari N, et al. Involvement of Munc18 isoforms in the regulation of granule exocytosis in neutrophils. Biochim Biophys Acta (BBA) Mol Cell Res. 2008;1783:1781–91.CrossRefGoogle Scholar
  3. Brochetta C, Suzuki R, Vita F, et al. Munc18-2 and syntaxin 3 control distinct essential steps in mast cell degranulation. J Immunol. 2014;192:41.CrossRefGoogle Scholar
  4. Cetica V, Santoro A, Gilmour KC, et al. STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5. J Med Genet. 2010;47:595.CrossRefGoogle Scholar
  5. Cetica V, Sieni E, Pende D, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol. 2016;137:188–96.e4.CrossRefGoogle Scholar
  6. Côte M, Ménager MM, Burgess A, et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119:3765–73.CrossRefGoogle Scholar
  7. Degar B. Familial hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 2015;29:903–13.CrossRefGoogle Scholar
  8. Dieckmann NMG, Hackmann Y, Aricò M, Griffiths GM. Munc18-2 is required for syntaxin 11 localization on the plasma membrane in cytotoxic T-lymphocytes. Traffic. 2015;16:1330–41.CrossRefGoogle Scholar
  9. Esmaeilzadeh H, Bemanian MH, Nabavi M, et al. Novel patient with late-onset familial hemophagocytic lymphohistiocytosis with STXBP2 mutations presenting with autoimmune hepatitis, neurological manifestations and infections associated with hypogammaglobulinemia. J Clin Immunol. 2015;35:22–5.CrossRefGoogle Scholar
  10. Filipovich AH, Chandrakasan S. Pathogenesis of hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 2015;29:895–902.CrossRefGoogle Scholar
  11. Gutierrez BA, Chavez MA, Rodarte AI, et al. Munc18-2, but not Munc18-1 or Munc18-3, controls compound and single-vesicle–regulated exocytosis in mast cells. J Biol Chem. 2018;293:7148–59.CrossRefGoogle Scholar
  12. Hackmann Y, Graham SC, Ehl S, et al. Syntaxin binding mechanism and disease-causing mutations in Munc18-2. Proc Natl Acad Sci. 2013;110:E4482.CrossRefGoogle Scholar
  13. Henter J-I, Aricò M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 1997;28:342–7.CrossRefGoogle Scholar
  14. Henter J-I, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.CrossRefGoogle Scholar
  15. Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47.CrossRefGoogle Scholar
  16. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118:4041–52.CrossRefGoogle Scholar
  17. Machaczka M, Klimkowska M, Chiang SCC, et al. Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations. Haematologica. 2013;98:760.CrossRefGoogle Scholar
  18. Martin-Verdeaux S, Pombo I, Iannascoli B, et al. Evidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis. J Cell Sci. 2003;116:325.CrossRefGoogle Scholar
  19. Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood. 2010;116:2635–43.CrossRefGoogle Scholar
  20. Mosa MH, Nicolle O, Maschalidi S, et al. Dynamic formation of microvillus inclusions during enterocyte differentiation in Munc18-2–deficient intestinal organoids. Cell Mol Gastroenterol Hepatol. 2018;6:477–93.e1.CrossRefGoogle Scholar
  21. Nikiforow S. The role of hematopoietic stem cell transplantation in treatment of hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 2015;29:943–59.CrossRefGoogle Scholar
  22. Pagel J, Beutel K, Lehmberg K, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood. 2012;119:6016–24.CrossRefGoogle Scholar
  23. Seo JJ. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: recent advances and controversies. Blood Res. 2015;50:131–9.CrossRefGoogle Scholar
  24. Sieni E, Cetica V, Mastrodicasa E, et al. Familial hemophagocytic lymphohistiocytosis: a model for understanding the human machinery of cellular cytotoxicity. Cell Mol Life Sci. 2012;69:29–40.CrossRefGoogle Scholar
  25. Spessott WA, Sanmillan ML, McCormick ME, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood. 2015;125:1566–77.CrossRefGoogle Scholar
  26. Spessott WA, Sanmillan ML, McCormick ME, Kulkarni VV, Giraudo CG. SM protein Munc18-2 facilitates transition of Syntaxin 11-mediated lipid mixing to complete fusion for T-lymphocyte cytotoxicity. Proc Natl Acad Sci. 2017;114:E2176.CrossRefGoogle Scholar
  27. Stepensky P, Bartram J, Barth TF, et al. Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations. Pediatr Blood Cancer. 2013;60:1215–22.CrossRefGoogle Scholar
  28. Tang Y-M, Xu X-J. Advances in hemophagocytic lymphohistiocytosis: pathogenesis, early diagnosis/differential diagnosis, and treatment. TheScientificWorldJOURNAL. 2011;11Google Scholar
  29. Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol. 2013;161:609–22.CrossRefGoogle Scholar
  30. Vogel GF, van Rijn JM, Krainer IM, et al. Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations. JCI Insight. 2018;2Google Scholar
  31. Zhao XW, Gazendam RP, Drewniak A, et al. Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations. Blood. 2013;122:109–11.CrossRefGoogle Scholar
  32. zur Stadt U, Rohr J, Seifert W, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85:482–92.CrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Section of Immunology, Allergy, and RetrovirologyTexas Children’s HospitalHoustonUSA
  2. 2.William T. Shearer Center for Human ImmunobiologyTexas Children’s HospitalHoustonUSA
  3. 3.Department of PediatricsBaylor College of MedicineHoustonUSA

Section editors and affiliations

  • Javier Chinen
    • 1
  1. 1.Division of Allergy and Immunology, Department of PediatricsBaylor College of Medicine, Texas Children’s HospitalThe WoodlandsUSA