Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

• Published in: Nature communications Vol. 9; no. 1; pp. 4250 - 17
• Main Authors: Latham, Sharissa L., Ehmke, Nadja, Reinke, Patrick Y. A., Taft, Manuel H., Eicke, Dorothee, Reindl, Theresia, Stenzel, Werner, Lyons, Michael J., Friez, Michael J., Lee, Jennifer A., Hecker, Ramona, Frühwald, Michael C., Becker, Kerstin, Neuhann, Teresa M., Horn, Denise, Schrock, Evelin, Niehaus, Indra, Sarnow, Katharina, Grützmann, Konrad, Gawehn, Luzie, Klink, Barbara, Rump, Andreas, Chaponnier, Christine, Figueiredo, Constanca, Knöfler, Ralf, Manstein, Dietmar J., Di Donato, Nataliya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/51; 14/19; 14/28; 14/63; 38/39; 45/91; 631/208/2489/144; 631/250/232/2051/1339; 631/80/128/1653; 692/699/1541; 82/29; Actin; Actins - genetics; Actins - metabolism; Anisotropy; Blood Platelets - metabolism; Cells, Cultured; Cytoskeleton; Cytoskeleton - metabolism; Developmental disabilities; Exons; Exons - genetics; Female; Fibroblasts; Genotype; Genotypes; Germ-Line Mutation - genetics; Humanities and Social Sciences; Humans; Male; Megakaryocytes; Megakaryocytes - metabolism; Microencephaly; Molecular modelling; multidisciplinary; Mutation; Mutation - genetics; Patients; Phenotype; Phenotypes; Platelets; Proteins; Science; Science (multidisciplinary); Thrombocytes; Thrombocytopenia; Thrombocytopenia - genetics; Thrombocytopenia - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06713-0

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. Genetic variants in ACTB and ACTG1 have been associated with Baraitser-Winter Cerebrofrontofacial syndrome. Here, the authors report of a syndromic thrombocytopenia caused by variants in ACTB exons 5 or 6 that compromise the organization and coupling of the cytoskeleton, leading to impaired platelet maturation.