1. ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder
- Author
-
Cuvertino, Sara, Stuart, Helen M., Chandler, Kate E., Roberts, Neil A., Armstrong, Ruth, Bernardini, Laura, Bhaskar, Sanjeev, Callewaert, Bert, Clayton-Smith, Jill, Davalillo, Cristina Hernando, Deshpande, Charu, Devriendt, Koenraad, Digilio, Maria C., Dixit, Abhijit, Edwards, Matthew, Friedman, Jan M., Gonzalez-Meneses, Antonio, Joss, Shelagh, Kerr, Bronwyn, Lampe, Anne Katrin, Langlois, Sylvie, Lennon, Rachel, Loget, Philippe, Ma, David Y. T., Mcgowan, Ruth, Des Medt, Maryse, O'Sullivan, James, Odent, Sylvie, Parker, Michael J., Pebrel-Richard, Céline, Petit, Florence, Stark, Zornitza, Stockler-Ipsiroglu, Sylvia, Tinschert, Sigrid, Vasudevan, Pradeep, Villa, Olaya, White, Susan M., Zahir, Farah R., Study, Ddd, Woolf, Adrian S., Banka, Siddharth, University of Manchester [Manchester], Regional Genetic Service, St Mary's Hospital, Manchester, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Hospital, Center for Medical Genetics [Ghent], Ghent University Hospital, Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Guy's Hospital [London], Centre for Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Nottingham City Hospital, Western Sydney University (UWS), University of British Columbia (UBC), Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), University of Edinburgh, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Department of Clinical Genetics, Leicester Royal Infirmary, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sheffield Children's Hospital, CHU Clermont-Ferrand, CHU de Lille, Genetic Health Services Victoria, Innsbruck Medical University [Austria] (IMU), University Hospitals of Leicester, University of Melbourne, Victorian Clinical Genetics Services, University of Northern British Columbia (UNBC), Hamad Bin Khalifa University (HBKU), The Wellcome Trust Sanger Institute [Cambridge], L002744/1, Medical Research Council UK, Central Manchester University Hospitals NHS Foundation Trust, Kidney Research UK, NIHR, Academy of Medical Sciences, 16-17/10, Newlife Foundation, 629396, Kabuki Research Fund, Wellcome Trust, HICF-1009-003, Health Innovation Challenge Fund, WT098051, Wellcome Trust Sanger Institute, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Western Sydney University, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], University Hospitals Leicester-University Hospitals Leicester, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Sheffield Children's NHS Foundation Trust, University Hospitals Leicester, University of Northern British Columbia [Prince George] (UNBC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)
- Subjects
DYNAMICS ,Male ,Developmental Disabilities ,CYTOSKELETON ,Haploinsufficiency ,Mice ,Medicine and Health Sciences ,RNA, Small Interfering ,Child ,Frameshift Mutation ,developmental disorder ,ARCHITECTURE ,Cell Cycle ,Coloboma ,Malformations of Cortical Development ,Codon, Nonsense ,Child, Preschool ,DELAY ,malformations ,Female ,RNA Interference ,Abnormalities ,Multiple ,Adult ,Adolescent ,Small Interfering ,Young Adult ,WINTER CEREBROFRONTOFACIAL SYNDROME ,Report ,Intellectual Disability ,Humans ,Animals ,Abnormalities, Multiple ,MALFORMATIONS ,β-actin ,Preschool ,Codon ,Aged ,Cell Proliferation ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Infant, Newborn ,Biology and Life Sciences ,Infant ,Facies ,ACTB ,Newborn ,NUCLEAR ACTIN ,Actins ,BETA-ACTIN ,Nonsense ,DE-NOVO MUTATIONS ,MECHANICS ,chromatin ,RNA ,Gene Deletion - 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. ispartof: American Journal of Human Genetics vol:101 issue:6 pages:1021-1033 ispartof: location:United States status: published
- Published
- 2017