Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?
Maria Chiriaco, Giorgiana Madalina Ursu, Donato Amodio, Nicola Cotugno, Stefano Volpi, Francesco Berardinelli, Simone Pizzi, Cristina Cifaldi, Matteo Zoccolillo, Ignazia Prigione, Silvia Di Cesare, Carmela Giancotta, Elisa Anastasio, Beatrice Rivalta, Lucia Pacillo, Paola Zangari, Alessandro G Fiocchi, Andrea Diociaiuti, Alessandro Bruselles, Francesca Pantaleoni, Andrea Ciolfi, Valentina D'Oria, Giuseppe Palumbo, Marco Gattorno, Maya El Hachem, Jean-Pierre de Villartay, Andrea Finocchi, Paolo Palma, Paolo Rossi, Marco Tartaglia, Alessandro Aiuti, Antonio Antoccia, Gigliola Di Matteo, Caterina Cancrini
Author Information
Maria Chiriaco: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Giorgiana Madalina Ursu: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Donato Amodio: Academic Department of Pediatrics, Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, Rome, Italy.
Nicola Cotugno: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Stefano Volpi: Center for Autoinflammatory Diseases and Immunodeficiencies, Scientific Institute for Research and Healthcare (IRCCS) Istituto Giannina Gaslini and University of Genoa, Genoa, Italy.
Francesco Berardinelli: Laboratory of Neurodevelopment, Neurogenetics and Molecular Neurobiology, Scientific Institute for Research and Healthcare (IRCCS) Santa Lucia Foundation, Rome, Italy.
Simone Pizzi: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Cristina Cifaldi: Academic department of Pediatrics, Research Unit of Primary Immunodeficiencies, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Matteo Zoccolillo: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Ignazia Prigione: Center for Autoinflammatory Diseases and Immunodeficiencies, Scientific Institute for Research and Healthcare (IRCCS) Istituto Giannina Gaslini and University of Genoa, Genoa, Italy.
Silvia Di Cesare: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Carmela Giancotta: Academic Department of Pediatrics, Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, Rome, Italy.
Elisa Anastasio: Department of Medical and Surgical Sciences, Pediatrics Unit, University "Magna Graecia", Catanzaro, Italy.
Beatrice Rivalta: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Lucia Pacillo: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Paola Zangari: Academic Department of Pediatrics, Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, Rome, Italy.
Alessandro G Fiocchi: Pediatric Allergology Unit, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Andrea Diociaiuti: Dermatology Unit, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Alessandro Bruselles: Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Francesca Pantaleoni: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Andrea Ciolfi: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Valentina D'Oria: Research Laboratories, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Giuseppe Palumbo: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Marco Gattorno: Center for Autoinflammatory Diseases and Immunodeficiencies, Scientific Institute for Research and Healthcare (IRCCS) Istituto Giannina Gaslini and University of Genoa, Genoa, Italy.
Maya El Hachem: Dermatology Unit, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Jean-Pierre de Villartay: Université de Paris, Imagine Institute, Laboratory "Genome Dynamics in the Immune System", INSERM UMR 1163, F-75015, Paris, France.
Andrea Finocchi: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Paolo Palma: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Paolo Rossi: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Marco Tartaglia: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.
Alessandro Aiuti: San Raffaele Telethon Institute for Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), San Raffaele Scientific Institute, Milan, Italy.
Antonio Antoccia: Department of Science, Roma Tre University, Rome, Italy.
Gigliola Di Matteo: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Caterina Cancrini: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott-Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients' cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions.
