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 Gawehn, Barbara Klink, Andreas Rump, Christine Chaponnier, Constanca Figueiredo, Ralf Knöfler, Dietmar J. Manstein () and Nataliya Di Donato ()
Additional contact information
Sharissa L. Latham: Hannover Medical School
Nadja Ehmke: Charité-Universitätsmedizin Berlin
Patrick Y. A. Reinke: Hannover Medical School
Manuel H. Taft: Hannover Medical School
Dorothee Eicke: Hannover Medical School
Theresia Reindl: Hannover Medical School
Werner Stenzel: Charité-Universitätsmedizin Berlin
Michael J. Lyons: Greenwood Genetic Center, Greenwood
Michael J. Friez: Greenwood Genetic Center, Greenwood
Jennifer A. Lee: Greenwood Genetic Center, Greenwood
Ramona Hecker: Medical Faculty of TU Dresden
Michael C. Frühwald: Children’s Hospital Augsburg
Kerstin Becker: Medical Genetics Center
Teresa M. Neuhann: Medical Genetics Center
Denise Horn: Charité-Universitätsmedizin Berlin
Evelin Schrock: Institute for Clinical Genetics
Indra Niehaus: Institute for Clinical Genetics
Katharina Sarnow: Institute for Clinical Genetics
Konrad Grützmann: National Center for Tumor Diseases Dresden
Luzie Gawehn: Institute for Clinical Genetics
Barbara Klink: Institute for Clinical Genetics
Andreas Rump: Institute for Clinical Genetics
Christine Chaponnier: University of Geneva
Constanca Figueiredo: Hannover Medical School
Ralf Knöfler: Medical Faculty of TU Dresden
Dietmar J. Manstein: Hannover Medical School
Nataliya Di Donato: Institute for Clinical Genetics

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06713-0

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