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.
Nat Commun. 2017 Apr 3;8:14816. doi: 10.1038/ncomms14816.
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.
人肌动蛋白相关蛋白 2/3 复合物（Arp2/3）对于肌动蛋白丝分支是必需的，它有两个 ARPC1 组成型异构体，其中 ARPC1B 在血细胞中表达显著。在这里，我们在一名患有微血小板减少症、嗜酸性粒细胞增多症和炎症性疾病的儿童中发现 ARPC1B（p.Val91Trpfs*30）纯合移码突变。血小板裂解物中没有 ARPC1B 蛋白，Arp2/3 复合物大大减少。在具有类似症状和 ARPC1B 缺乏的另一位无关患者中鉴定出错义 ARPC1B 突变。ARPC1B 缺陷型血小板是微血小板，类似于在 Wiskott-Aldrich 综合征中看到的血小板，表现出与 Arp2/3 功能丧失一致的异常扩散。巨核细胞中 ARPC1B 的敲除导致原血小板形成减少，并且正如在患者的血小板中观察到的那样，ARPC1A 表达增加。因此，ARPC1B 的缺失产生了一组独特的血小板异常，并且与影响该同工型占主导地位的造血/免疫细胞谱系的造血/免疫症状相关。与最近的实验研究一致，我们的研究结果表明 ARPC1 同工型不能在功能上互换。
