Skip to main content

Advertisement

SpringerLink
Log in

Molecular and Phenotypic Characterization of Nine Patients with STAT1 GOF Mutations in China

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

Abstract

Purpose

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates cellular responses to interferons (IFNs) and other cytokines and growth factors in diverse cell types. STAT1 gain-of-function (GOF) mutations result in an unexpectedly wide range of clinical features. It remains unclear why STAT1 GOF mutations result in such a broad spectrum of phenotypes.

Methods

We analyzed the clinical, molecular, and phenotypic characteristics of nine Chinese patients with STAT1 GOF mutations.

Results

This study enrolled nine patients with STAT1 GOF mutations including five novel mutations. We discuss the molecular and phenotypic characterization such as unique Penicillium marneffei lymphadenitis. Patients with STAT1 GOF mutations had defects in both innate and adaptive immunity, including impaired T cell receptor (TCR) diversity; reduced numbers of naïve and effector memory CD4+ T cells, memory B cells, and NK cells; and defects in the production of IL-17A and IFN-γ. In addition, experiments with primary immune cells revealed that enhanced STAT1 phosphorylation resulted from not only lower rates of STAT1 dephosphorylation but also increased total STAT1 expression.

Conclusions

Our report provides the first comprehensive overview of the molecular genetics, clinical heterogeneity, and underlying immunological abnormalities of patients with STAT1 GOF mutations in China. In further study, to find the relationship between different STAT1 GOF mutations and clinical phenotype as well as the mechanism of increased total STAT1 expression will be needed.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. García-Sastre A, Biron CA. Type 1 interferons and the virus-host relationship: a lesson in détente. Science. 2006;312:879–82.

    Article  Google Scholar 

  2. van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LAB, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365:54–61.

    Article  Google Scholar 

  3. Liu L, Okada S, Kong X-F, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208:1635–48.

    Article  CAS  Google Scholar 

  4. Smeekens SP, Plantinga TS, van de Veerdonk FL, Heinhuis B, Hoischen A, Joosten LAB, et al. STAT1 hyperphosphorylation and defective IL12r/IL23r signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS One. 2011;6:1–7.

    Article  Google Scholar 

  5. Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131:1624–34.

    Article  CAS  Google Scholar 

  6. Soltész B, Tóth B, Shabashova N, Bondarenko A, Okada S, Cypowyj S, et al. New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. J Med Genet. 2013;50:567–78.

    Article  Google Scholar 

  7. Sharfe N, Nahum A, Newell A, Dadi H, Ngan B, Pereira SL, et al. Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. J Allergy Clin Immunol. 2014;133:807–17.

    Article  CAS  Google Scholar 

  8. Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, et al. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti–IL-17F autoantibody. J Immunol. 2014;193:4880–7.

    Article  CAS  Google Scholar 

  9. Depner M, Fuchs S, Raabe J, Frede N, Glocker C, Doffinger R, et al. The extended clinical phenotype of 26 patients with chronic mucocutaneous candidiasis due to gain-of-function mutations in STAT1. J Clin Immunol. 2016;36:73–84.

    Article  CAS  Google Scholar 

  10. Toubiana J, Okada S, Hiller J, Oleastro M, Gomez ML, Becerra JCA, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–64.

    Article  CAS  Google Scholar 

  11. Zheng J, van de Veerdonk FL, Crossland KL, Smeekens SP, Chan CM, Al Shehri T, et al. Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). Eur J Immunol. 2015;45(10):2834–46.

    Article  CAS  Google Scholar 

  12. Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, et al. Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. J Leukoc Biol. 2014;95(4):667–76.

    Article  Google Scholar 

  13. Zhang Y, Ma CA, Lawrence MG, Break TJ, O’Connell MP, Lyons JJ, et al. PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients. J Exp Med. 2017;214(9):2523–33.

    Article  Google Scholar 

  14. Bernasconi AR, Yancoski J, Villa M, Oleastro MM, Galicchio M, Rossi JG. Increased STAT1 amounts correlate with the phospho-STAT1 level in STAT1 gain-of-function defects. J Clin Immunol. 2018;38(7):745–7.

    Article  Google Scholar 

  15. Bloomfield M, Kanderová V, Paračková Z, Vrabcová P, Svatoň M, Froňková E, et al. Utility of ruxolitinib in a child with chronic mucocutaneous candidiasis caused by a novel STAT1 gain-of-function mutation. J Clin Immunol. 2018;38(5):589–601.

    Article  CAS  Google Scholar 

  16. Hiller J, Hagl B, Effner R, Puel A, Schaller M, Mascher B, et al. STAT1 gain-of-function and dominant negative STAT3 mutations impair IL-17 and IL-22 immunity associated with CMC. J Investig Dermatol. 2018;138(3):711–4.

    Article  CAS  Google Scholar 

  17. Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol. 2015;136(4):993–1006.

    Article  CAS  Google Scholar 

  18. Vargas-Hernández A, Mace EM, Zimmerman O, Zerbe CS, Freeman AF, Rosenzweig S, et al. Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2018;141(6):2142–55.

    Article  Google Scholar 

  19. Langerak AW, Van Den Beemd R, Wolvers-Tettero ILM, Boor PPC, Van Lochem EG, Hooijkaas H, et al. Molecular and flow cytometric analysis of the Vβ repertoire for clonality assessment in mature TCRαβ t-cell proliferations. Blood. 2001;98(1):165–73.

    Article  CAS  Google Scholar 

  20. Ding Y, Zhou L, Xia Y, Wang W, Wang Y, Li L, et al. Reference values for peripheral blood lymphocyte subsets of healthy children in China. J Allergy Clin Immunol. 2018;142:970–973.e8.

    Article  Google Scholar 

  21. Kobbe R, Kolster M, Fuchs S, Schulze-Sturm U, Jenderny J, Kochhan L, et al. Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation. Gene. 2016;586(2):234–8.

    Article  CAS  Google Scholar 

  22. Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, et al. Severe early-onset combined immunodeficiency due to heterozygous gain-of-function mutations in STAT1. J Clin Immunol. 2016;36(7):641–8.

    Article  CAS  Google Scholar 

  23. Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629–40.

    Article  CAS  Google Scholar 

  24. Lee PP, Lau YL. Cellular and molecular defects underlying invasive fungal infections—revelations from endemic mycoses. Front Immunol. 2017;8:735.

    Article  Google Scholar 

  25. Lee PPW, Mao H, Yang W, Chan KW, Ho MHK, Lee TL, et al. Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal-dominant gain-of-phosphorylation STAT1 mutations. J Allergy Clin Immunol. 2014;133(3):894–6.

    Article  CAS  Google Scholar 

  26. Hori T, Ohnishi H, Teramoto T, Tsubouchi K, Naiki T, Hirose Y, et al. Autosomal-dominant chronic mucocutaneous candidiasis with stat1-mutation can be complicated with chronic active hepatitis and hypothyroidism. J Clin Immunol. 2012;32(6):1213–20.

    Article  CAS  Google Scholar 

  27. Takasu N, Noh JY. Hashimoto’s thyroiditis: TGAb, TPOAb, TRAb and recovery from hypothyroidism. Expert Rev Clin Immunol. 2008;4(2):221–37.

    Article  CAS  Google Scholar 

  28. Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24(4):364–78.

    Article  CAS  Google Scholar 

  29. Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010;62(1):234–44.

    Article  CAS  Google Scholar 

  30. Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther. 2012;14(6):R255.

    Article  CAS  Google Scholar 

  31. Zhu C, Jie M, Liu Y, Tong J, Tian J, Chen J, et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 2012;97(3):943–50.

    Article  CAS  Google Scholar 

  32. Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol. 2012;8(6):337–47.

    Article  CAS  Google Scholar 

  33. Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, et al. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018;141(3):1050–9.

    Article  CAS  Google Scholar 

  34. Okajima M, Wada T, Nishida M, Yokoyama T, Nakayama Y, Hashida Y, et al. Analysis of T cell receptor Vβ diversity in peripheral CD4+ and CD8+ T lymphocytes in patients with autoimmune thyroid diseases. Clin Exp Immunol. 2009;155(2):166–72.

    Article  CAS  Google Scholar 

  35. Bristeau-Leprince A, Mateo V, Lim A, Magerus-Chatinet A, Solary E, Fischer A, et al. Human TCR / + CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted V TCR diversity and are clonally related to CD8+ T cells. J Immunol. 2014;181:440–8.

    Article  Google Scholar 

  36. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911.

    Article  CAS  Google Scholar 

  37. Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131:1611–1623.e3.

    Article  CAS  Google Scholar 

  38. Yuasa K, Hijikata T. Distal regulatory element of the STAT1 gene potentially mediates positive feedback control of STAT1 expression. Genes Cells. 2016;21(1):25–40.

    Article  CAS  Google Scholar 

  39. van de Veerdonk FL, Netea MG. Treatment options for chronic mucocutaneous candidiasis. J Infect. 2016;72:S56–60.

    Article  Google Scholar 

  40. Weinacht KG, Charbonnier LM, Alroqi F, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel STAT1 gain of function mutation. 2017;139(5):1629–1640.e2.

  41. Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, et al. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations. J Allergy Clin Immunol. 2018;141:704–717.e5.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families for their kind cooperation in this study. We thank the members of the laboratory for technical assistance. We thank the doctors and nurses for supporting this project. We also thank Satoshi Okada for technical assistance.

Funding

This work was supported by the Public Welfare Scientific Research Project of China (201402012).

Author information

Authors and Affiliations

  1. Department of Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

    Xuemei Chen, Qiling Xu, Lu Yang, Zhi Chen, Ting Zeng, Xiuhong Xue, Tao Xu, Yanping Wang, Yanjun Jia, Qin Zhao, Fangfang Liang, Yunfei An & Xiaodong Zhao

  2. Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Xuemei Chen, Qiling Xu, Lu Yang, Zhi Chen, Ting Zeng, Xiuhong Xue, Tao Xu, Yanping Wang, Yanjun Jia, Qin Zhao, Fangfang Liang, Yunfei An & Xiaodong Zhao

  3. Department of Pediatric Rheumatology and Immunology, Zhongshan Boai Hospital Affiliated Southern Medical University, Zhongshan, 528400, China

    Xiaolin Li

  4. Department of Rheumatology and Immunology, Shenzhen Children’s Hospital, Shenzhen, 518000, China

    Linlin Wang & Jun Yang

  5. Department of Rheumatology and Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Junfeng Wu, Xuemei Tang, Yunfei An & Xiaodong Zhao

Authors
  1. Xuemei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiling Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaolin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linlin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ting Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiuhong Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yanjun Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Junfeng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fangfang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xuemei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yunfei An
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xiaodong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XM.C., YF.A., and XD.Z. designed the study and wrote the manuscript; XM.C., L.Y., Z.C., T.Z., XH.X., T.X., YP.W., YJ.J., Q.Z., and JF.W. did the experiments and analyzed patients’ data; XM.C., QL.X., XL.L, LL.W., FF.L, J.Y, XM.T., and YF.A. followed the patients; all authors reviewed the manuscript before publication.

Corresponding authors

Correspondence to Yunfei An or Xiaodong Zhao.

Ethics declarations

Informed consent was obtained from all individual participants included in the study. This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the ethics committee of Chongqing Medical University.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Xu, Q., Li, X. et al. Molecular and Phenotypic Characterization of Nine Patients with STAT1 GOF Mutations in China. J Clin Immunol 40, 82–95 (2020). https://doi.org/10.1007/s10875-019-00688-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-019-00688-3

Keywords

Search

Navigation