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Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia.

  • Latham SL Institute for Biophysical Chemistry, Hannover Medical School, Hannover, 30625, Germany. Latham.Sharissa@mh-hannover.de.
  • Ehmke N Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, 13353, Germany.
  • Reinke PYA Institute for Biophysical Chemistry, Hannover Medical School, Hannover, 30625, Germany.
  • Taft MH Institute for Biophysical Chemistry, Hannover Medical School, Hannover, 30625, Germany.
  • Eicke D Institute for Transfusion Medicine, Hannover Medical School, Hannover, 30625, Germany.
  • Reindl T Institute for Biophysical Chemistry, Hannover Medical School, Hannover, 30625, Germany.
  • Stenzel W Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, 10117, Germany.
  • Lyons MJ Greenwood Genetic Center, Greenwood, South Carolina, SC, 29646, USA.
  • Friez MJ Greenwood Genetic Center, Greenwood, South Carolina, SC, 29646, USA.
  • Lee JA Greenwood Genetic Center, Greenwood, South Carolina, SC, 29646, USA.
  • Hecker R Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty of TU Dresden, Dresden, 01307, Germany.
  • Frühwald MC Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, 86156, Germany.
  • Becker K Medical Genetics Center, Munich, 80335, Germany.
  • Neuhann TM Medical Genetics Center, Munich, 80335, Germany.
  • Horn D Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, 13353, Germany.
  • Schrock E Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany.
  • Niehaus I Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany.
  • Sarnow K Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany.
  • Grützmann K Core Unit for Molecular Tumor Diagnostics, National Center for Tumor Diseases Dresden, Dresden, 01307, Germany.
  • Gawehn L Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany.
  • Klink B Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany.
  • Rump A Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany.
  • Chaponnier C Department of Pathology-Immunology, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland.
  • Figueiredo C Institute for Transfusion Medicine, Hannover Medical School, Hannover, 30625, Germany.
  • Knöfler R Department of Paediatric Haemostaseology, Medical Faculty of TU Dresden, Dresden, 01307, Germany.
  • Manstein DJ Institute for Biophysical Chemistry, Hannover Medical School, Hannover, 30625, Germany. Manstein.Dietmar@mh-hannover.de.
  • Di Donato N Institute for Clinical Genetics, TU Dresden, Dresden, 01307, Germany. Nataliya.didonato@uniklinikum-dresden.de.
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  • 2018-10-14
Published in:
  • Nature communications. - 2018
Actins
Blood Platelets
Cells, Cultured
Cytoskeleton
Exons
Female
Genotype
Germ-Line Mutation
Humans
Male
Megakaryocytes
Mutation
Phenotype
Thrombocytopenia
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/43681
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