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

Jie Pan, Aleixo M Muise, John H Brumell, Rae S M Yeung, Chaim M Roifman, Julia Upton, Ronald M Laxer, Ernest Cutz, Ryan Murchie, Irene Lara-Corrales, Gabriella Leung, Walter H A Kahr, Cornelia Thoeni, Qi Li, Ren Li, Ling Li, Richard W Lo, Chang Hua Chen, Marko Drobac, Neil Warner, Abdul Elkadri, Fred G Pluthero

Journal: Nature communications 2018;8():14816

PMID: 28368018

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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.

Address: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.; Division of Haematology/Oncology, Department of Paediatrics, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.; SickKids Inflammatory Bowel Disease Center and Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.; Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.; Division of Rheumatology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.; Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.; Division of Immunology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

DOI: 10.1038/ncomms14816

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MeSH Terms: Actin-Related Protein 2-3 Complex, Actins, Blood Platelet Disorders, Blood Platelets, Bone Marrow Cells, Cell Shape, Disease Susceptibility, Fibrinogen, Gene Knockout Techniques, Humans, Inflammation, Megakaryocytes, Mutation, Vasculitis, Wiskott-Aldrich Syndrome