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

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-Corrales, Ryan Murchie, Ernest Cutz, Ronald M. Laxer, Julia Upton, Chaim M. Roifman, Rae S. M. Yeung, John H Brumell and Aleixo M Muise ()
Additional contact information
Walter H. A. Kahr: Cell Biology Program, Research Institute, Hospital for Sick Children
Fred G. Pluthero: Cell Biology Program, Research Institute, Hospital for Sick Children
Abdul Elkadri: Cell Biology Program, Research Institute, Hospital for Sick Children
Neil Warner: Cell Biology Program, Research Institute, Hospital for Sick Children
Marko Drobac: Cell Biology Program, Research Institute, Hospital for Sick Children
Chang Hua Chen: Cell Biology Program, Research Institute, Hospital for Sick Children
Richard W. Lo: Cell Biology Program, Research Institute, Hospital for Sick Children
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
Cornelia Thoeni: Cell Biology Program, Research Institute, Hospital for Sick Children
Jie Pan: Cell Biology Program, Research Institute, Hospital for Sick Children
Gabriella Leung: Cell Biology Program, Research Institute, Hospital for Sick Children
Irene Lara-Corrales: The Hospital for Sick Children
Ryan Murchie: Cell Biology Program, Research Institute, Hospital for Sick Children
Ernest Cutz: The Hospital for Sick Children
Ronald M. Laxer: University of Toronto, The Hospital for Sick Children
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
John H Brumell: Cell Biology Program, Research Institute, Hospital for Sick Children
Aleixo M Muise: Cell Biology Program, Research Institute, Hospital for Sick Children

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14816

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