Nature Communications (Jun 2023)
Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling
- Cristiane J. Nunes-Santos,
- HyeSun Kuehn,
- Brigette Boast,
- SuJin Hwang,
- Douglas B. Kuhns,
- Jennifer Stoddard,
- Julie E. Niemela,
- Danielle L. Fink,
- Stefania Pittaluga,
- Mones Abu-Asab,
- John S. Davies,
- Valarie A. Barr,
- Tomoki Kawai,
- Ottavia M. Delmonte,
- Marita Bosticardo,
- Mary Garofalo,
- Magda Carneiro-Sampaio,
- Raz Somech,
- Mohammad Gharagozlou,
- Nima Parvaneh,
- Lawrence E. Samelson,
- Thomas A. Fleisher,
- Anne Puel,
- Luigi D. Notarangelo,
- Bertrand Boisson,
- Jean-Laurent Casanova,
- Beata Derfalvi,
- Sergio D. Rosenzweig
Affiliations
- Cristiane J. Nunes-Santos
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- HyeSun Kuehn
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- Brigette Boast
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- SuJin Hwang
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- Douglas B. Kuhns
- Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research
- Jennifer Stoddard
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- Julie E. Niemela
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- Danielle L. Fink
- Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research
- Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Mones Abu-Asab
- Electron Microscopy Laboratory, Biological Imaging Core, National Eye Institute, National Institutes of Health
- John S. Davies
- Predictive Toxicology Department of Safety Assessment, Genentech
- Valarie A. Barr
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Tomoki Kawai
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- Ottavia M. Delmonte
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- Marita Bosticardo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- Mary Garofalo
- Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- Magda Carneiro-Sampaio
- Children’s Hospital, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP)
- Raz Somech
- Pediatric Department A and Immunology Service, Edmond and Lily Safra Children’s Hospital
- Mohammad Gharagozlou
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Children’s Medical Centre, University of Medical Sciences
- Nima Parvaneh
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Children’s Medical Centre, University of Medical Sciences
- Lawrence E. Samelson
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Thomas A. Fleisher
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University
- Luigi D. Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University
- Beata Derfalvi
- Department of Pediatrics, Division of Immunology, Dalhousie University and IWK Health Center
- Sergio D. Rosenzweig
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health
- DOI
- https://doi.org/10.1038/s41467-023-39272-0
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 12
Abstract
Abstract We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)−6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.
