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Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

Author

Listed:
  • Walter H. A. Kahr

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    University of Toronto and The Hospital for Sick Children
    University of Toronto)

  • Fred G. Pluthero

    (Cell Biology Program, Research Institute, Hospital for Sick Children)

  • Abdul Elkadri

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children
    Institute of Medical Science, University of Toronto)

  • Neil Warner

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children)

  • Marko Drobac

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    University of Toronto)

  • Chang Hua Chen

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    University of Toronto)

  • Richard W. Lo

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    University of Toronto)

  • Ling Li

    (Cell Biology Program, Research Institute, Hospital for Sick Children)

  • Ren Li

    (Cell Biology Program, Research Institute, Hospital for Sick Children)

  • Qi Li

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children)

  • Cornelia Thoeni

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children)

  • Jie Pan

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children)

  • Gabriella Leung

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children)

  • Irene Lara-Corrales

    (The Hospital for Sick Children)

  • Ryan Murchie

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children)

  • Ernest Cutz

    (The Hospital for Sick Children)

  • Ronald M. Laxer

    (University of Toronto, The Hospital for Sick Children
    University of Toronto)

  • Julia Upton

    (University of Toronto, The Hospital for Sick Children)

  • Chaim M. Roifman

    (University of Toronto, The Hospital for Sick Children)

  • Rae S. M. Yeung

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Institute of Medical Science, University of Toronto
    University of Toronto, The Hospital for Sick Children
    University of Toronto)

  • John H Brumell

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children
    Institute of Medical Science, University of Toronto
    University of Toronto)

  • Aleixo M Muise

    (Cell Biology Program, Research Institute, Hospital for Sick Children
    University of Toronto
    Hepatology, and Nutrition, University of Toronto, Hospital for Sick Children
    Institute of Medical Science, University of Toronto)

Abstract

Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two ARPC1 component isoforms, with ARPC1B prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in ARPC1B (p.Val91Trpfs*30). Platelet lysates reveal no ARPC1B protein and greatly reduced Arp2/3 complex. Missense ARPC1B mutations are identified in an unrelated patient with similar symptoms and ARPC1B deficiency. ARPC1B-deficient platelets are microthrombocytes similar to those seen in Wiskott–Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of ARPC1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased ARPC1A expression. Thus loss of ARPC1B produces a unique set of platelet abnormalities, and is associated with haematopoietic/immune symptoms affecting cell lineages where this isoform predominates. In agreement with recent experimental studies, our findings suggest that ARPC1 isoforms are not functionally interchangeable.

Suggested Citation

  • Walter H. A. Kahr & Fred G. Pluthero & Abdul Elkadri & Neil Warner & Marko Drobac & Chang Hua Chen & Richard W. Lo & Ling Li & Ren Li & Qi Li & Cornelia Thoeni & Jie Pan & Gabriella Leung & Irene Lara, 2017. "Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14816
    DOI: 10.1038/ncomms14816
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