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Clinical and functional spectrum of RAC2-related immunodeficiency

Donkó, Ágnes, Sharapova, Svetlana O., Kabat, Juraj, Ganesan, Sundar, Hauck, Fabian H., Bergerson, Jenna R. E., Marois, Louis, Abbott, Jordan, Moshous, Despina, Williams, Kelli W., Campbell, Nicholas, Martin, Paul L., Lagresle-Peyrou, Chantal, Trojan, Timothy, Kuzmenko, Natalia B., Deordieva, Ekaterina A., Raykina, Elena V., Abers, Michael S., Abolhassani, Hassan, Barlogis, Vincent, Milla, Carlos, Hall, Geoffrey, Mousallem, Talal, Church, Joseph, Kapoor, Neena, Cros, Guilhem, Chapdelaine, Hugo, Franco-Jarava, Clara, Lopez-Lerma, Ingrid, Miano, Maurizio, Leiding, Jennifer W., Klein, Christoph, Stasia, Marie José, Fischer, Alain, Hsiao, Kuang-Chih, Martelius, Timi, Sepännen, Mikko R. J., Barmettler, Sara, Walter, Jolan, Masmas, Tania N., Mukhina, Anna A., Falcone, Emilia Liana, Kracker, Sven, Shcherbina, Anna, Holland, Steven M., Leto, Thomas L., Hsu, Amy P.·2024·Blood
DOI 10.1182/blood.2023022098
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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.

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Research works printed but not linked: 35

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Cited by

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Metadata

Authors
Donkó, Á., Sharapova, S. O., Kabat, J., Ganesan, S., Hauck, F. H., Bergerson, J. R. E., Marois, L., Abbott, J., Moshous, D., Williams, K. W., Campbell, N., Martin, P. L., Lagresle-Peyrou, C., Trojan, T., Kuzmenko, N. B., Deordieva, E. A., Raykina, E. V., Abers, M. S., Abolhassani, H., Barlogis, V., Milla, C., Hall, G., Mousallem, T., Church, J., Kapoor, N., Cros, G., Chapdelaine, H., Franco-Jarava, C., Lopez-Lerma, I., Miano, M., Leiding, J. W., Klein, C., Stasia, M. J., Fischer, A., Hsiao, K.-C., Martelius, T., Sepännen, M. R. J., Barmettler, S., Walter, J., Masmas, T. N., Mukhina, A. A., Falcone, E. L., Kracker, S., Shcherbina, A., Holland, S. M., Leto, T. L., & Hsu, A. P.
Affiliations
  • 1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
  • 2Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  • 3Research Technologies Branch, Biological Imaging Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
  • 4Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
  • 5Department of Medicine, Centre Hospitalier Universitaire de Montréal and Institut de Recherches Cliniques de Montréal, Université de Montréal, Montreal, QC, Canada
  • 7University of Colorado School of Medicine, Department of Pediatrics, Section of Allergy and Immunology, Children’s Hospital of Colorado, Aurora, CO
  • 8Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris Centre Université de Paris, Paris, France
  • 10Department of Pediatrics, Medical University of South Carolina, Charleston, SC
  • 11Hôpital Enfant Jésus, CHU de Québec, Québec, QC, Canada
  • 12Division of Transplant and Cellular Therapy, Duke University Medical School, Durham, NC
  • 13Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France
  • 15Allergy Partners of Oklahama, Stillwater, OK
  • 16D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
  • 17Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • 19Pediatric Hematology Unit, La Timone University Hospital, Marseille, France
  • 20Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA
  • 21Department of Pediatrics, Division of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC
  • 22Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC
  • 23Pediatric Allergy/Immunology, Children’s Hospital Los Angeles, Los Angeles, CA
  • 25Division of Hematology, Oncology and Blood and Marrow Transplant, Children’s Hospital Los Angeles, Los Angeles, CA
  • 26Department of Medicine, Université de Montreal, Montreal, QC, Canada
  • 28Department of Immunology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
  • 29Haematology Unit, Scientific Institute for Research, Hospitalization and Healthcare Istituto Giannina Gaslini, Genoa, Italy
  • 30Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD
  • 32Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig Maximilian University Munich, Munich, Germany
  • 33Centre Hospitalier Universitaire Grenoble Alpes, Pôle de Biologie, Centre Diagnostic et Recherche sur la Granulomatose Septique Chronique, Grenoble, France
  • 35Université Paris Cité, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France
  • 36Department of Immunology, Starship Child Health, Te Whatu Ora, Auckland, New Zealand
  • 38Inflammation Center/Infectious Diseases, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
  • 39Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
  • 43Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA
  • 44University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL
  • 45Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, The Child and Adolescent Department, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 46Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada
  • 49Université Paris Cité, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2024-04-11
Volume
143
Issue
15
Pages
1476-1487
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood.2023022098
Cited by
32
References
5
Language
en
Update notices
erratum (2024-09-05)

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