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Clinical and Functional Spectrum of Rac2-Related Immunodeficiency Publisher Pubmed



Donko A1 ; Sharapova SO2 ; Kabat J3 ; Ganesan S3 ; Hauck FH4 ; Bergerson JRE1 ; Marois L5, 6 ; Abbott J7 ; Moshous D8, 9 ; Williams KW10 ; Campbell N11 ; Martin PL12 ; Lagreslepeyrou C13, 14 ; Trojan T15 Show All Authors
Authors
  1. Donko A1
  2. Sharapova SO2
  3. Kabat J3
  4. Ganesan S3
  5. Hauck FH4
  6. Bergerson JRE1
  7. Marois L5, 6
  8. Abbott J7
  9. Moshous D8, 9
  10. Williams KW10
  11. Campbell N11
  12. Martin PL12
  13. Lagreslepeyrou C13, 14
  14. Trojan T15
  15. Kuzmenko NB16
  16. Deordieva EA16
  17. Raykina EV16
  18. Abers MS1
  19. Abolhassani H17, 18
  20. Barlogis V19
  21. Milla C20
  22. Hall G21
  23. Mousallem T22
  24. Church J23, 24
  25. Kapoor N25
  26. Cros G26, 27, 47
  27. Chapdelaine H26, 27, 47
  28. Francojarava C28
  29. Lopezlerma I28
  30. Miano M29
  31. Leiding JW30, 31
  32. Klein C32
  33. Stasia MJ33, 34
  34. Fischer A35
  35. Hsiao KC36, 37
  36. Martelius T38
  37. Sepannen MRJ39, 40, 41, 42
  38. Barmettler S43
  39. Walter J44
  40. Masmas TN45
  41. Mukhina AA16
  42. Falcone EL26, 46, 47, 48
  43. Kracker S35
  44. Shcherbina A16
  45. Holland SM1
  46. Leto TL1
  47. Hsu AP1
Show Affiliations
Authors Affiliations
  1. 1. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
  2. 2. Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  3. 3. Research Technologies Branch, Biological Imaging Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
  4. 4. Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany
  5. 5. Department of Medicine, Centre Hospitalier Universitaire de Montreal and Institut de Recherches Cliniques de Montreal, Universite de Montreal, Montreal, QC, Canada
  6. 6. Department of Medecine, Centre Hospitalier Universitaire de Quebec, Universite de Laval, Quebec, QC, Canada
  7. 7. University of Colorado School of Medicine, Department of Pediatrics, Section of Allergy and Immunology, Children's Hospital of Colorado, Aurora, CO, United States
  8. 8. Pediatric Hematology-Immunology and Rheumatology Department, Hopital Necker-Enfants Malades, Assistance Publique – Hopitaux de Paris Centre Universite de Paris, Paris, France
  9. 9. Universite de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Paris, France
  10. 10. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
  11. 11. Hopital Enfant Jesus, CHU de Quebec, Quebec, QC, Canada
  12. 12. Division of Transplant and Cellular Therapy, Duke University Medical School, Durham, NC, United States
  13. 13. Universite Paris Cite, Imagine Institute, INSERM UMR 1163, Paris, France
  14. 14. Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique–Hopitaux de Paris, INSERM, Paris, France
  15. 15. Allergy Partners of Oklahama, Stillwater, OK, United States
  16. 16. D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  17. 17. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
  18. 18. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  19. 19. Pediatric Hematology Unit, La Timone University Hospital, Marseille, France
  20. 20. Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA, United States
  21. 21. Department of Pediatrics, Division of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC, United States
  22. 22. Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, United States
  23. 23. Pediatric Allergy/Immunology, Children's Hospital Los Angeles, Los Angeles, CA, United States
  24. 24. Clinical Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States
  25. 25. Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, United States
  26. 26. Department of Medicine, Universite de Montreal, Montreal, QC, Canada
  27. 27. Institut de Recherches Cliniques de Montreal, Montreal, QC, Canada
  28. 28. Department of Immunology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  29. 29. Haematology Unit, Scientific Institute for Research, Hospitalization and Healthcare Istituto Giannina Gaslini, Genoa, Italy
  30. 30. Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, United States
  31. 31. Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
  32. 32. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University Munich, Munich, Germany
  33. 33. Centre Hospitalier Universitaire Grenoble Alpes, Pole de Biologie, Centre Diagnostic et Recherche sur la Granulomatose Septique Chronique, Grenoble, France
  34. 34. Universite Grenoble Alpes, Centre National de le Recherche Scientifique, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, France
  35. 35. Universite Paris Cite, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France
  36. 36. Department of Immunology, Starship Child Health, Te Whatu Ora, Auckland, New Zealand
  37. 37. Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
  38. 38. Inflammation Center/Infectious Diseases, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
  39. 39. Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
  40. 40. ERN-RITA Core Center Member, RITAFIN, Helsinki, Finland
  41. 41. Rare Disease Center and Pediatric Research Center, Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
  42. 42. Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
  43. 43. Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, United States
  44. 44. University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
  45. 45. Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, The Child and Adolescent Department, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  46. 46. Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada
  47. 47. Department of Medicine, Universite de Montreal, Montreal, QC, Canada
  48. 48. Department of Microbiology, Infectious Diseases and Immunology, Universite de Montreal, Montreal, QC, Canada

Source: Blood Published:2024


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. © 2024
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