title: Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease.
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.
authors.affiliation: 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.
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Fred G
authors.initials: FG
authors.lastname: Pluthero
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Abdul
authors.initials: A
authors.lastname: Elkadri
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Neil
authors.initials: N
authors.lastname: Warner
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Marko
authors.initials: M
authors.lastname: Drobac
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Chang Hua
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Lo
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Ren
authors.initials: R
authors.lastname: Li
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Thoeni
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Jie
authors.initials: J
authors.lastname: Pan
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leung
authors.affiliation: Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Irene
authors.initials: I
authors.lastname: Lara-Corrales
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murchie
authors.affiliation: Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.affiliation: 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.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Laxer
authors.affiliation: Division of Immunology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Julia
authors.initials: J
authors.lastname: Upton
authors.affiliation: Division of Immunology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.|Division of Rheumatology, 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.
authors.forename: Rae S M
authors.initials: RS
authors.lastname: Yeung
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|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.
authors.forename: Aleixo M
authors.identifier: 0000-0001-9624-3346
authors.initials: AM
authors.lastname: Muise
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000172:deficiency* / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D001791:Blood Platelet Disorders / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048430:Cell Shape; D004198:Disease Susceptibility; D005340:Fibrinogen / Q000494:pharmacology; D055786:Gene Knockout Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D014657:Vasculitis / Q000473:pathology; D014923:Wiskott-Aldrich Syndrome / Q000473:pathology
chemical_list: C460821:ARPC1B protein, human; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D005340:Fibrinogen