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A Novel RAC2 Mutation Causing Combined Immunodeficiency

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Abstract

Purpose

Ras-related C3 botulinum toxin substrate 2 (RAC2) acts as a molecular switch and has crucial roles in cell signaling and actin dynamics. A broad spectrum of genetic RAC2 mutations can cause various types of primary immunodeficiency, with complete penetrance. Here, we report a novel heterozygous missense mutation in RAC2 with incomplete penetrance, and the associated phenotypes, in a Chinese family.

Methods

Immunological phenotype was detected by flow cytometry. T cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs) were assessed by real-time quantitative PCR. Gene mutations were detected by whole-exome sequencing (WES) and confirmed by Sanger sequencing.

Results

The proband was an 11-year-old girl who presented with recurrent respiratory infections, bronchiectasis, persistent Epstein-Barr virus viremia, infectious mononucleosis, encephalitis, and cutaneous human papillomavirus infections. Laboratory analyses revealed increased serum IgG and decreased IgM levels, reduced naïve CD4+ and CD8+ T cells, an inverted CD4+/CD8+ ratio, and low TREC and KREC numbers. The mutation resulted in increased production of reactive oxygen species, while impaired actin polarization in neutrophils; diminished proliferative responses, increased cytokine production and a dysregulated phenotype in T lymphocytes; as well as accelerated apoptosis and hyperactivity of AKT in HL-60 human leukemia cells. WES identified a c.44G > A mutation in RAC2 resulting in a p.G15D substitution. Despite sharing the same mutation as the proband, her father suffered from recurrent respiratory infections and bronchiectasis, and had similar immunological defects, whereas her sister was apparently healthy, other than cutaneous human papillomavirus infections, and only mild immunological defects were detected preliminarily.

Conclusions

Our findings broaden the clinical and genetic spectra of RAC2 mutations and underline the importance of RAC2 gain-of-function mutations with complete or incomplete penetrance.

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Data Availability

The data analyzed in the current study are available from the corresponding author on reasonable request.

References

  1. Bokoch GM. Regulation of innate immunity by Rho GTPases. Trends Cell Biol. 2005;15(3):163–71.

    Article  CAS  Google Scholar 

  2. Williams DA, Zheng Y, Cancelas JA. Rho GTPases and regulation of hematopoietic stem cell localization. Methods Enzymol. 2008;439:365–93.

    Article  CAS  Google Scholar 

  3. Pernis AB. Rho GTPase-mediated pathways in mature CD4+ T cells. Autoimmun Rev. 2009;8(3):199–203.

    Article  CAS  Google Scholar 

  4. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9(9):690–701.

    Article  CAS  Google Scholar 

  5. Mulloy JC, Cancelas JA, Filippi MD, et al. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010;115(5):936–47.

    Article  CAS  Google Scholar 

  6. El Masri R, Delon J. RHO GTPases: from new partners to complex immune syndromes. Nat Rev Immunol. 2021;21(8):499–513.

    Article  Google Scholar 

  7. Troeger A, Williams DA. Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders. Exp Cell Res. 2013;319(15):2375–83.

    Article  CAS  Google Scholar 

  8. Lougaris V, Baronio M, Gazzurelli L, et al. RAC2 and primary human immune deficiencies. J Leukoc Biol. 2020;108(2):687–96.

    Article  CAS  Google Scholar 

  9. Ambruso DR, Knall C, Abell AN, et al. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A. 2000;97(9):4654–9.

    Article  CAS  Google Scholar 

  10. Williams DA, Tao W, Yang F, et al. Dominant negative mutation of the hematopoietic specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood. 2000;96(5):1646–54.

    CAS  Google Scholar 

  11. Accetta D, Syverson G, Bonacci B, et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol. 2011;127:535–8.

    Article  CAS  Google Scholar 

  12. Alkhairy OK, Rezaei N, Graham RR, et al. RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol. 2015;135(5):1380-4.e1-5.

    Article  CAS  Google Scholar 

  13. Lougaris V, Chou J, Beano A, et al. A monoallelic activating mutation in RAC2 resulting in a combined immunodeficiency. J Allergy Clin Immunol. 2019;143(4):1649-1653.e3.

    Article  CAS  Google Scholar 

  14. Hsu AP, Donkó A, Arrington ME, et al. Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood. 2019;133(18):1977–88.

    Article  CAS  Google Scholar 

  15. Sharapova SO, Haapaniemi E, Sakovich IS, et al. Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections. Clin Immunol. 2019;205:1–5.

    Article  CAS  Google Scholar 

  16. Smits BM, Lelieveld PHC, Ververs FA, et al. A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease. Clin Immunol. 2020;212:108248.

    Article  CAS  Google Scholar 

  17. Lagresle-Peyrou C, Olichon A, Sadek H, et al. A gain-of- function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency. Haematologica. 2021;106(2):404–11.

    Article  CAS  Google Scholar 

  18. Stern H, Donkó A, Shapiro T, et al. A novel RAC2 variant presenting as severe combined immunodeficiency. J Clin Immunol. 2021;41(2):473–6.

    Article  CAS  Google Scholar 

  19. Ding Y, Zhou L, Xia Y, et al. Reference values for peripheral blood lymphocyte subsets of healthy children in China. J Allergy Clin Immunol. 2018;142(3):970-973.e8.

    Article  Google Scholar 

  20. Sottini A, Serana F, Bertoli D, et al. Simultaneous quantification of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs) by real-time PCR. J Vis Exp. 2014;94:52184.

    Google Scholar 

  21. Zhang L, Chen Z, Li W, et al. Combined immunodeficiency caused by a novel de novo gain-of-function RAC2 mutation. J Clin Immunol. 2022 May 21. https://doi.org/10.1007/s10875-022-01288-4. Online ahead of print.

  22. Honda F, Kano H, Kanegane H, et al. The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils. Nat Immunol. 2012;13(4):369–78.

    Article  CAS  Google Scholar 

  23. Bunney TD, Opaleye O, Roe SM, et al. Structural insights into formation of an active signaling complex between Rac and phospholipase C Gamma 2. Mol Cell. 2009;34(2):223–33.

    Article  CAS  Google Scholar 

  24. Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

    Article  Google Scholar 

  25. Tabellini G, Baronio M, Patrizi O, et al. The RAC2-PI3K axis regulates human NK cell maturation and function. Clin Immunol. 2019;208:108257.

    Article  CAS  Google Scholar 

  26. Latour S, Fischer A. Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases. Immunol Rev. 2019;291(1):174–89.

    Article  CAS  Google Scholar 

  27. Cohen JI. Herpesviruses in the activated phosphatidylinositol-3-kinase-δ syndrome. Front Immunol. 2018;9:237.

    Article  Google Scholar 

  28. Lucas CL, Chandra A, Nejentsev S, et al. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702–14.

    Article  CAS  Google Scholar 

  29. Campa CC, Ciraolo E, Ghigo A, et al. Crossroads of PI3K and Rac pathways. Small GTPases. 2015;6(2):71–80.

    Article  CAS  Google Scholar 

  30. Weeks JK, Helton KJ, Conley ME, et al. Diffuse CNS vasculopathy with chronic Epstein-Barr virus infection in X-linked lymphoproliferative disease. AJNR Am J Neuroradiol. 2006;27(4):884–6.

    CAS  Google Scholar 

  31. Kim JH, Joo BE, Koh SB. Serial diffusion-weighted MR imaging findings in a patient with Epstein-Barr virus encephalitis. J Neurol. 2007;254(11):1616–8.

    Article  Google Scholar 

  32. Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606.e4.

    Article  CAS  Google Scholar 

  33. Crequer A, Troeger A, Patin E, et al. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J Clin Invest. 2012;122(9):3239–47.

    Article  CAS  Google Scholar 

  34. Li X, Bu X, Lu B, et al. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002;22(4):1158–71.

    Article  CAS  Google Scholar 

  35. Gruber C, Bogunovic D. Incomplete penetrance in primary immunodefciency: a skeleton in the closet. Hum Genet. 2020;139(6–7):745–57.

    Article  Google Scholar 

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Acknowledgements

We are grateful to the patient and her family for their continuous cooperation in this study. We thank the members of the laboratory for their technical assistance, and the doctors and nurses for their generous support of this project.

Funding

This work was supported by the Postgraduate Tutor Team Project of Chongqing Municipal Education Commission (Education Research and Development Program of Chongqing: 2019–9-66). L.Z. was also supported by the Talent Program of Hunan Children’s Hospital (grant number: 1233), and supported by the Clinical Research (Translation) Center of Hunan Children’s Hospital.

Author information

Author notes

  1. Liang Zhang and Ge Lv contributed equally.

Authors and Affiliations

  1. Department of Nephrology, Rheumatology and Immunology, Hunan Children’s Hospital, Changsha, Hunan, China

    Liang Zhang & Zhihui Li

  2. The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, China

    Liang Zhang, Yu Peng & Zhihui Li

  3. 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, China

    Ge Lv, Lu Yang, Junjie Chen, Yunfei An, Zhiyong Zhang, Xuemei Tang & Xiaodong Zhao

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

    Ge Lv, Lu Yang, Junjie Chen, Yunfei An, Zhiyong Zhang, Xuemei Tang & Xiaodong Zhao

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

    Ge Lv, Lu Yang, Junjie Chen, Yunfei An, Zhiyong Zhang, Xuemei Tang & Xiaodong Zhao

  6. Department of Pediatrics Research Institute, Hunan Children’s Hospital, Changsha, Hunan, China

    Yu Peng

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  1. Liang Zhang
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Contributions

ZX.D. and ZH.L. designed the study; L.Z., G.L., L.Y., and JJ.C. performed the experiments; Y.P. performed the genetic analysis; L.Z. and G.L. collected and analyzed the data, and wrote the manuscript; ZY.Z., YF.A., and XM.T. provided some crucial clinical data. All the authors reviewed the manuscript before it was submitted.

Corresponding authors

Correspondence to Zhihui Li or Xiaodong Zhao.

Ethics declarations

Ethics Approval

This study was approved by the Medical Ethics Committee of Hunan Children’s Hospital (Approval number: HCHLL-2022–10).

Consent to Participate

Informed consent was obtained from the patient and her parents, in accordance with the Declaration of Helsinki.

Consent to Publish

Written informed consent was obtained from all participants included in the study.

Competing Interests

The authors declare no competing interests.

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Zhang, L., Lv, G., Peng, Y. et al. A Novel RAC2 Mutation Causing Combined Immunodeficiency. J Clin Immunol 43, 229–240 (2023). https://doi.org/10.1007/s10875-022-01373-8

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  • DOI: https://doi.org/10.1007/s10875-022-01373-8

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