Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Sharissa L. Latham*, Nadja Ehmke, Patrick Y.A. Reinke, Manuel H. Taft, Dorothee Eicke, Theresia Reindl, Werner Stenzel, Michael J. Lyons, Michael J. Friez, Jennifer A. Lee, Ramona Hecker, Michael C. Frühwald, Kerstin Becker, Teresa M. Neuhann, Denise Horn, Evelin Schrock, Indra Niehaus, Katharina Sarnow, Konrad Grützmann, Luzie GawehnBarbara Klink, Andreas Rump, Christine Chaponnier, Constanca Figueiredo, Ralf Knöfler, Dietmar J. Manstein, Nataliya Di Donato

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)


Germline mutations in the ubiquitously expressed ACTB, which encodes β-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 β-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 β-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.

Original languageEnglish
Article number4250
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2018
Externally publishedYes


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