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

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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.

No MeSH data available.


Bone marrow megakaryocyte morphology from Patient 1.Diagnostic bone marrow aspirate showing normal megakaryocytes with multilobed nuclei and large cytoplasm indicating normal morphology. Images were acquired from marrow smear preparations after Wright–Giemsa staining. Magnification × 60, bar=10μm.
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f8: Bone marrow megakaryocyte morphology from Patient 1.Diagnostic bone marrow aspirate showing normal megakaryocytes with multilobed nuclei and large cytoplasm indicating normal morphology. Images were acquired from marrow smear preparations after Wright–Giemsa staining. Magnification × 60, bar=10μm.

Mentions: We observed adequate MK numbers and normal morphology in a bone marrow biopsy sample from Patient 1 (Fig. 8). This indicates that MK depletion is not a cause of thrombocytopenia, although the possibility of abnormal proplatelet formation cannot be ruled out. Platelet counts were always low in Patient 1, low (for example, 79 × 109 l−1) to normal in Patient 2, and normal in Patient 3 (Table 1). The microthrombocytes we observed in all three patients suggest that decreased ARPC1B in MKs affects the cytoskeletal dynamics of platelet formation4248 sufficiently to influence platelet size. The thrombocytopenia observed in Patient 1 indicates that total loss of ARPC1B leads to depression of platelet production and/or increased clearance.


Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease
Bone marrow megakaryocyte morphology from Patient 1.Diagnostic bone marrow aspirate showing normal megakaryocytes with multilobed nuclei and large cytoplasm indicating normal morphology. Images were acquired from marrow smear preparations after Wright–Giemsa staining. Magnification × 60, bar=10μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382316&req=5

f8: Bone marrow megakaryocyte morphology from Patient 1.Diagnostic bone marrow aspirate showing normal megakaryocytes with multilobed nuclei and large cytoplasm indicating normal morphology. Images were acquired from marrow smear preparations after Wright–Giemsa staining. Magnification × 60, bar=10μm.
Mentions: We observed adequate MK numbers and normal morphology in a bone marrow biopsy sample from Patient 1 (Fig. 8). This indicates that MK depletion is not a cause of thrombocytopenia, although the possibility of abnormal proplatelet formation cannot be ruled out. Platelet counts were always low in Patient 1, low (for example, 79 × 109 l−1) to normal in Patient 2, and normal in Patient 3 (Table 1). The microthrombocytes we observed in all three patients suggest that decreased ARPC1B in MKs affects the cytoskeletal dynamics of platelet formation4248 sufficiently to influence platelet size. The thrombocytopenia observed in Patient 1 indicates that total loss of ARPC1B leads to depression of platelet production and/or increased clearance.

View Article: PubMed Central - PubMed

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.

No MeSH data available.