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

Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two component isoforms, with prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in duanyu37C1B (p.Val91Trpfs*30). Platelet lysates reveal no duanyu37C1B protein and greatly reduced Arp2/3 complex. Missense duanyu37C1B mutations are identified in an unrelated patient with similar symptoms and duanyu37C1B deficiency. platelets are microthrombocytes similar to those seen in Wiskott-Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of duanyu37C1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased expression. Thus loss of duanyu37C1B 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 duanyu37C1 isoforms are not functionally interchangeable.

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