Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nat Commun 2017 Apr 03;8:14816
Date
04/04/2017Pubmed ID
28368018Pubmed Central ID
PMC5382316DOI
10.1038/ncomms14816Scopus ID
2-s2.0-85016791743 (requires institutional sign-in at Scopus site) 209 CitationsAbstract
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.
Author List
Kahr WH, Pluthero FG, Elkadri A, Warner N, Drobac M, Chen CH, Lo RW, Li L, Li R, Li Q, Thoeni C, Pan J, Leung G, Lara-Corrales I, Murchie R, Cutz E, Laxer RM, Upton J, Roifman CM, Yeung RS, Brumell JH, Muise AMAuthor
Abdul Aziz Elkadri MD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Actin-Related Protein 2-3 ComplexActins
Blood Platelet Disorders
Blood Platelets
Bone Marrow Cells
Cell Shape
Disease Susceptibility
Fibrinogen
Gene Knockout Techniques
Humans
Inflammation
Megakaryocytes
Mutation
Vasculitis
Wiskott-Aldrich Syndrome
