2. Academic Validation
  3. ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

  • Am J Hum Genet. 2017 Dec 7;101(6):1021-1033. doi: 10.1016/j.ajhg.2017.11.006.
Sara Cuvertino 1,  Helen M Stuart 2,  Kate E Chandler 3,  Neil A Roberts 4,  Ruth Armstrong 5,  Laura Bernardini 6,  Sanjeev Bhaskar 3,  Bert Callewaert 7,  Jill Clayton-Smith 2,  Cristina Hernando Davalillo 8,  Charu Deshpande 9,  Koenraad Devriendt 10,  Maria C Digilio 11,  Abhijit Dixit 12,  Matthew Edwards 13,  Jan M Friedman 14,  Antonio Gonzalez-Meneses 15,  Shelagh Joss 16,  Bronwyn Kerr 3,  Anne Katrin Lampe 17,  Sylvie Langlois 14,  Rachel Lennon 18,  Philippe Loget 19,  David Y T Ma 14,  Ruth McGowan 16,  Maryse Des Medt 10,  James O'Sullivan 2,  Sylvie Odent 20,  Michael J Parker 21,  Céline Pebrel-Richard 22,  Florence Petit 23,  Zornitza Stark 24,  Sylvia Stockler-Ipsiroglu 14,  Sigrid Tinschert 25,  Pradeep Vasudevan 26,  Olaya Villa 8,  Susan M White 27,  Farah R Zahir 28,  DDD Study 29,   Adrian S Woolf 30,  Siddharth Banka 31
Affiliations

Affiliations

  • 1 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, M13 9PL Manchester, UK.
  • 2 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, M13 9PL Manchester, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, M13 9WL Manchester, UK.
  • 3 Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, M13 9WL Manchester, UK.
  • 4 Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, M13 9PL, Manchester, UK.
  • 5 East Anglian Medical Genetics Service, Department of Clinical Genetics, Addenbrooke's Hospital, CB2 0QQ, Cambridge, UK.
  • 6 Cytogenetics Unit, Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy.
  • 7 Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • 8 Quantitative Genomic Medicine Laboratories (qGenomics), 08950 Barcelona, Spain.
  • 9 Clinical Genetics Department, Guy's Hospital, SE1 9RT London, UK.
  • 10 Center for Human genetics, Katholieke Universiteit Leuven and University Hospital Leuven, B-3000 Leuven, Belgium.
  • 11 Medical Genetics, Bambino Gesù Pediatric Hospital, IRCCS, 00165 Rome, Italy.
  • 12 Department of Clinical Genetics, Nottingham City Hospital, NG5 1PB Nottingham, UK.
  • 13 Department of Paediatrics, School of Medicine, University of Western Sydney, NSW 2751, New South Wales, Australia.
  • 14 Department of Medical Genetics, University of British Columbia, BC V6T 1Z4 Vancouver, Canada.
  • 15 Servicio de Pediatría, Hospital Viamed Santa Ángela de la Cruz, 41014 Sevilla, Spain.
  • 16 West of Scotland Genetics Service, Queen Elizabeth University Hospital, G51 4TF Glasgow, UK.
  • 17 South East of Scotland Clinical Genetic Department, Western General Hospital, EH4 2XU Edinburgh, UK.
  • 18 Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, M13 9PL Manchester, UK.
  • 19 Service d'Anatomie Pathologique, Hôpital Pontchaillou, University Rennes 1, 35000 Rennes, France.
  • 20 Service de Génétique Clinique, Centre de Référence "Maladies Rares" CLAD-Ouest, Hôpital SUD, University Rennes 1, UMR 6290, 35000 Rennes, France.
  • 21 Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, S20 1NZ Sheffield, UK.
  • 22 Service de Cytogénétique Médicale, Centre Hospitalier Régional Clermont-Ferrand, 63000 Clermont-Ferrand, France.
  • 23 Service de Genetique Clinique, Centre Hospitalier Régional Lille, 59000 Lille, France.
  • 24 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, VIC 3052 Melbourne, Australia.
  • 25 Zentrum Medizinische Genetik, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 26 Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, LE1 5WW Leicester, UK.
  • 27 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, VIC 3052 Melbourne, Australia; Department of Paediatrics, University of Melbourne, VIC 3010, Melbourne, Australia.
  • 28 Department of Medical Genetics, University of British Columbia, BC V6T 1Z4 Vancouver, Canada; Qatar Biomedical Research Institute, Hamad Bin Khalifa University, 34110 Doha, Qatar.
  • 29 Wellcome Trust Sanger Institute, CB10 1SA Cambridge, UK.
  • 30 Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, M13 9PL, Manchester, UK; Department of Nephrology, Royal Manchester Children's Hospital, Manchester Academic Health Science Centre, M13 9WL Manchester, UK.
  • 31 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, M13 9PL Manchester, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, M13 9WL Manchester, UK. Electronic address: siddharth.banka@manchester.ac.uk.
PMID: 29220674 DOI: 10.1016/j.ajhg.2017.11.006
Abstract

ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

Keywords

ACTB; chromatin; developmental disorder; malformations; β-actin.

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