Skip to main content

Advertisement

SpringerLink
Log in

Novel Syntaxin 11 Gene (STX11) Mutation in Three Argentinean Patients with Hemophagocytic Lymphohistiocytosis

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease with major diagnostic and therapeutic difficulties, basically comprising two different conditions: primary and secondary forms. Recent advances regarding molecular diagnosis may be useful to distinguish from one another, especially in sporadic cases starting in early infancy.

Materials and Methods

In this report, we evaluated three Argentinean patients with clinical suspicion of HLH, but without family history. We excluded mutations in the perforin gene but identified in the three patients a novel homozygous deletion (c. 581_584delTGCC; p.Leu194ProfsX2) in the gene-encoding syntaxin 11 (STX11), causing a premature termination codon.

Results and Conclusion

Each parent from the three unrelated families resulted heterozygous for this deletion confirming the diagnosis of familial hemophagocytic lymphohistiocytosis type 4. Patients shared the same single-nucleotide polymorphism profile in STX11 gene, and genotyping at ten microsatellites surrounding this gene support the presence of a single-haplotype block carrying the novel mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140:221–30.

    Article  CAS  PubMed  Google Scholar 

  2. Henter J-I, Arico M, Elinder Gimashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12:417–33.

    Article  CAS  PubMed  Google Scholar 

  3. Henter J-I, Horne AC, Arico M, Egeler M, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Article  PubMed  Google Scholar 

  4. Dufourcq-Lagelouse R, Jabado N, Le Deist F, Stephan JL, Souillet G, Bruin M, et al. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21–22 and evidence for heterogeneity. Am J Hum Genet. 1999;64:172–9.

    Article  CAS  PubMed  Google Scholar 

  5. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286:1957–9.

    Article  CAS  PubMed  Google Scholar 

  6. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc 13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115:461–73.

    Article  CAS  PubMed  Google Scholar 

  7. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter J-I, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14:827–34.

    Article  CAS  PubMed  Google Scholar 

  8. Prekeris R, Klumperman J, Scheller RH. Syntaxin 11 is an atypical SNARE abundant in the immune system. Eur J Cell Biol. 2000;79:771–80.

    Article  CAS  PubMed  Google Scholar 

  9. Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. 2005;203:165–79.

    Article  CAS  PubMed  Google Scholar 

  10. Bryceson YT, Rudd E, Zheng C, Edner J, Ma D, Wood SM, et al. Defective cytotoxic lymphocyte degranulation in syntaxin-11–deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood. 2007;110:1906–15.

    Article  CAS  PubMed  Google Scholar 

  11. Arneson LN, Brickshawana A, Segovis CM, Schoon RA, Dick CJ, Leibson PJ. Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol. 2007;179:3397–401.

    CAS  PubMed  Google Scholar 

  12. Zhang S, Ma D, Wang X, Celkan T, Nordenskjöld M, Henter JI, et al. Syntaxin-11 is expressed in primary human monocytes/macrophages and acts as a negative regulator of macrophage engulfment of apoptotic cells and IgG-opsonized target cells. Br J Haematol. 2008;142:469–79.

    Article  CAS  PubMed  Google Scholar 

  13. zur Stadt U, Beutel K, Kolberg S, Schneppenheim R, Kabisch H, Janka G, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11 and RAB27A. Hum Mut. 2006;27:62–8.

    Article  CAS  PubMed  Google Scholar 

  14. Rudd E, Ericson KG, Zheng C, Uysal Z, Özkan A, Gürgey A, et al. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J Med Genet. 2006;43:e14.

    Article  CAS  PubMed  Google Scholar 

  15. Horne A, Ramme KG, Rudd E, Zheng C, Wali Y, al-Lamki Z, et al. Characterization of PRF1, STX11 and UNC13D genotype–phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol. 2008;143:75–83.

    Article  PubMed  Google Scholar 

  16. Anderson HA, Roche PA. Phosphorylation regulates the delivery of MHC class II invariant chain complexes to antigen processing compartments. J Immunol. 1998;160:4850–8.

    CAS  PubMed  Google Scholar 

  17. Génin E, Tullio-Pelet A, Begeot F, Lyonnet S, Abel L. Estimating the age of rare disease mutations: the example of Triple-A syndrome. J Med Genet. 2004;41:445–9.

    Article  PubMed  Google Scholar 

  18. Yancoski J, Rocco C, Bernasconi A, Oleastro M, Bezrodnik L, Vrátnica C, et al. A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian susceptibility to mycobacterial diseases in European descendants. Infect Genet Evol. 2009;9:574–80.

    Article  CAS  PubMed  Google Scholar 

  19. Weber JL, Wong C. Mutation of human short tandem repeats. Hum Mol Genet. 1993;2:1123–8.

    Article  CAS  PubMed  Google Scholar 

  20. Valdez AC, Cabaniols J-P, Brown MJ, Roche PA. Syntaxin 11 is associated with SNAP-23 on late endosomes and the trans-Golgi network. J Cell Sci. 1999;112:845–54.

    CAS  PubMed  Google Scholar 

  21. Lee SM, Sumegi J, Villanueva J, Tabata Y, Zhang K, Chakraborty R, et al. Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr. 2006;149:134–7.

    Article  CAS  PubMed  Google Scholar 

  22. Tang BL, Low DY, Tan AE, Hong W. Syntaxin 10: a member of the syntaxin family localized to the trans-Golgi network. Biochem Biophys Res Commun. 1998;242:345–50.

    Article  CAS  PubMed  Google Scholar 

  23. Marcenaro S, Gallo F, Martini S, Santoro A, Griffiths GM, Aricó M, et al. Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13–4 defect and discriminates between genetic subtypes of the disease. Blood. 2006;108:2316–23.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by Agencia Nacional de Promoción Científica y Tecnológica (PICT2004 No. 21235). We wish to thank Verónica Goris for the expert handling of patient samples and Marianela Sanz for technical assistance in the detection of NK activity and CD107a.

Author information

Authors and Affiliations

  1. Servicio de Inmunologia y Reumatologia, Hospital de Pediatria Juan P Garrahan, Buenos Aires, Argentina

    Silvia Danielian, Natalia Basile, Emma Prieto, Jorge Rossi, Andrea Bernasconi, Matías Oleastro & Marta Zelazko

  2. Laboratorio de Biología Celular y Retrovirus, Hospital de Pediatria Juan P Garrahan, Buenos Aires, Argentina

    Carlos Rocco

  3. Servicio de Hematologia/Oncologia, Hospital de Pediatria Juan P Garrahan, Buenos Aires, Argentina

    Darío Barsotti & Jorge Braier

  4. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Paul A. Roche

Authors
  1. Silvia Danielian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Basile
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos Rocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emma Prieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jorge Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Darío Barsotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul A. Roche
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea Bernasconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matías Oleastro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marta Zelazko
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jorge Braier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia Danielian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Danielian, S., Basile, N., Rocco, C. et al. Novel Syntaxin 11 Gene (STX11) Mutation in Three Argentinean Patients with Hemophagocytic Lymphohistiocytosis. J Clin Immunol 30, 330–337 (2010). https://doi.org/10.1007/s10875-009-9350-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-009-9350-4

Keywords

Search

Navigation