Clinical and functional spectrum of RAC2-related immunodeficiency

Author:

Donkó Ágnes1,Sharapova Svetlana O.2ORCID,Kabat Juraj3,Ganesan Sundar3,Hauck Fabian H.4ORCID,Bergerson Jenna R. E.1,Marois Louis56ORCID,Abbott Jordan7ORCID,Moshous Despina89ORCID,Williams Kelli W.10ORCID,Campbell Nicholas11,Martin Paul L.12,Lagresle-Peyrou Chantal1314ORCID,Trojan Timothy15,Kuzmenko Natalia B.16,Deordieva Ekaterina A.16ORCID,Raykina Elena V.16,Abers Michael S.1ORCID,Abolhassani Hassan1718ORCID,Barlogis Vincent19ORCID,Milla Carlos20ORCID,Hall Geoffrey21ORCID,Mousallem Talal22ORCID,Church Joseph2324,Kapoor Neena25,Cros Guilhem2627,Chapdelaine Hugo2627ORCID,Franco-Jarava Clara28,Lopez-Lerma Ingrid28,Miano Maurizio29ORCID,Leiding Jennifer W.3031ORCID,Klein Christoph32,Stasia Marie José3334,Fischer Alain35,Hsiao Kuang-Chih3637ORCID,Martelius Timi38ORCID,Sepännen Mikko R. J.39404142ORCID,Barmettler Sara43,Walter Jolan44ORCID,Masmas Tania N.45ORCID,Mukhina Anna A.16ORCID,Falcone Emilia Liana464748,Kracker Sven49,Shcherbina Anna16,Holland Steven M.1,Leto Thomas L.1,Hsu Amy P.1ORCID

Affiliation:

1. 1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

2. 2Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus

3. 3Research Technologies Branch, Biological Imaging Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

4. 4Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

5. 5Department of Medicine, Centre Hospitalier Universitaire de Montréal and Institut de Recherches Cliniques de Montréal, Université de Montréal, Montreal, QC, Canada

6. 6Department of Medecine, Centre Hospitalier Universitaire de Québec, Université de Laval, Québec, QC, Canada

7. 7University of Colorado School of Medicine, Department of Pediatrics, Section of Allergy and Immunology, Children’s Hospital of Colorado, Aurora, CO

8. 8Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris Centre Université de Paris, Paris, France

9. 9Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Paris, France

10. 10Department of Pediatrics, Medical University of South Carolina, Charleston, SC

11. 11Hôpital Enfant Jésus, CHU de Québec, Québec, QC, Canada

12. 12Division of Transplant and Cellular Therapy, Duke University Medical School, Durham, NC

13. 13Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France

14. 14Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique–Hôpitaux de Paris, INSERM, Paris, France

15. 15Allergy Partners of Oklahama, Stillwater, OK

16. 16D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia

17. 17Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden

18. 18Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

19. 19Pediatric Hematology Unit, La Timone University Hospital, Marseille, France

20. 20Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA

21. 21Department of Pediatrics, Division of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC

22. 22Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC

23. 23Pediatric Allergy/Immunology, Children’s Hospital Los Angeles, Los Angeles, CA

24. 24Clinical Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA

25. 25Division of Hematology, Oncology and Blood and Marrow Transplant, Children’s Hospital Los Angeles, Los Angeles, CA

26. 26Department of Medicine, Université de Montreal, Montreal, QC, Canada

27. 27Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada

28. 28Department of Immunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain

29. 29Haematology Unit, Scientific Institute for Research, Hospitalization and Healthcare Istituto Giannina Gaslini, Genoa, Italy

30. 30Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD

31. 31Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL

32. 32Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig Maximilian University Munich, Munich, Germany

33. 33Centre Hospitalier Universitaire Grenoble Alpes, Pôle de Biologie, Centre Diagnostic et Recherche sur la Granulomatose Septique Chronique, Grenoble, France

34. 34Université Grenoble Alpes, Centre National de le Recherche Scientifique, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, France

35. 35Université Paris Cité, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France

36. 36Department of Immunology, Starship Child Health, Te Whatu Ora, Auckland, New Zealand

37. 37Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

38. 38Inflammation Center/Infectious Diseases, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland

39. 39Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland

40. 40ERN-RITA Core Center Member, RITAFIN, Helsinki, Finland

41. 41Rare Disease Center and Pediatric Research Center, Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland

42. 42Translational Immunology Research Program, University of Helsinki, Helsinki, Finland

43. 43Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA

44. 44University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL

45. 45Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, The Child and Adolescent Department, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

46. 46Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada

47. 47Department of Medicine, Université de Montréal, Montreal, QC, Canada

48. 48Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada

49. 49Université Paris Cité, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France

Abstract

Abstract Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Publisher

American Society of Hematology

Reference40 articles.

1. Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac2;Knaus;Science,1991

2. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics;Edwards;Nat Cell Biol,1999

3. Rac-mediated stimulation of phospholipase Cg2 amplifies B cell receptor-induced calcium signaling;Walliser;J Biol Chem,2015

4. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation;Ambruso;Proc Natl Acad Sci U S A,2000

5. Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency;Williams;Blood,2000

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