期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14816
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资金
- Crohn's and Colitis Canada (CCC)
- Canadian Association of Gastroenterology (CAG)
- Canadian Institute of Health Research (CIHR) Fellowship
- Research Institute of the Hospital for Sick Children, Toronto, Canada
- Ontario Graduate Scholarship
- Canadian Institutes of Health Research (CIHR) [MOP-81208, MOP-119450]
- CIHR Team grant [THC 135233]
- Arthritis Society of Canada
- Crohn's and Colitis Canada
- Jeffery Modell Foundation
- Immunodeficiency Canada distinguished Professorship
- Canadian Centre for Primary Immunodeficiency
- CIHR [MOP119457]
- Leona M. and Harry B. Helmsley Charitable Trust
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.
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