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Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Autor: Latham SL, Ehmke N, [...], Becker K, Neuhann T, et al.
Veröffentlichungsdatum: 12.10.2018

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Neurologie / Neuropädiatrie

Germline mutations in the ubiquitously expressed ACTB, which encodes beta-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fibroblasts, we  demonstrate cohort specific changes to beta-CYA filament populations, which include the enhanced recruitment of thrombocytopenia-associated actin binding proteins (ABPs). These perturbed interactions are supported by in silico modeling and are validated in disease-relevant thrombocytes. Co-examination of actin and microtubule cytoskeleton constituents in patient-derived megakaryocytes and thrombocytes indicates that these beta-CYA mutations inhibit the final stages of  platelet maturation by compromising microtubule organization. Our results define  an ACTB-associated clinical syndrome with a distinct genotype-phenotype correlation and delineate molecular mechanisms underlying thrombocytopenia in this patient cohort.

Nat Commun. 2018;9(1):4250.


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