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Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling

Author

Listed:
  • Cristiane J. Nunes-Santos

    (National Institutes of Health)

  • HyeSun Kuehn

    (National Institutes of Health)

  • Brigette Boast

    (National Institutes of Health)

  • SuJin Hwang

    (National Institutes of Health)

  • Douglas B. Kuhns

    (Frederick National Laboratory for Cancer Research)

  • Jennifer Stoddard

    (National Institutes of Health)

  • Julie E. Niemela

    (National Institutes of Health)

  • Danielle L. Fink

    (Frederick National Laboratory for Cancer Research)

  • Stefania Pittaluga

    (National Institutes of Health)

  • Mones Abu-Asab

    (National Institutes of Health)

  • John S. Davies

    (Predictive Toxicology Department of Safety Assessment, Genentech)

  • Valarie A. Barr

    (National Institutes of Health)

  • Tomoki Kawai

    (National Institutes of Health)

  • Ottavia M. Delmonte

    (National Institutes of Health)

  • Marita Bosticardo

    (National Institutes of Health)

  • Mary Garofalo

    (National Institutes of Health)

  • Magda Carneiro-Sampaio

    (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP))

  • Raz Somech

    (Edmond and Lily Safra Children’s Hospital
    The Jeffrey Modell Foundation Israeli Network for Primary Immunodeficiency
    Tel Aviv University)

  • Mohammad Gharagozlou

    (University of Medical Sciences)

  • Nima Parvaneh

    (University of Medical Sciences)

  • Lawrence E. Samelson

    (National Institutes of Health)

  • Thomas A. Fleisher

    (National Institutes of Health)

  • Anne Puel

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute)

  • Luigi D. Notarangelo

    (National Institutes of Health)

  • Bertrand Boisson

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute)

  • Jean-Laurent Casanova

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute
    Necker Hospital for Sick Children, AP-HP)

  • Beata Derfalvi

    (Dalhousie University and IWK Health Center)

  • Sergio D. Rosenzweig

    (National Institutes of Health)

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.

Suggested Citation

  • 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. Dav, 2023. "Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39272-0
    DOI: 10.1038/s41467-023-39272-0
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    References listed on IDEAS

    as
    1. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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