Contributors: University of Manchester Manchester; Regional Genetic Service, St Mary's Hospital, Manchester; East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital; Mendel Laboratory; Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza San Giovanni Rotondo (IRCCS); Center for Medical Genetics Ghent; Ghent University Hospital; Centre for Genomic Regulation - Centre de Regulació Genòmica Barcelona (CRG); Universitat Pompeu Fabra Barcelona (UPF)-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 = Bambino Gesù Children’s Hospital; Nottingham City Hospital; Western Sydney University; University of British Columbia (UBC); Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow); Queen Elizabeth University Hospital (Glasgow); University of Edinburgh (Edin.); Service d'anatomie et cytologie pathologiques Rennes = Anatomy and Cytopathology Rennes; Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Ponchaillou; Department of Clinical Genetics; Leicester Royal Infirmary; University Hospitals Leicester-University Hospitals Leicester; CLAD Ouest; Centre Hospitalier Universitaire Rennes; Institut de Génétique et Développement de Rennes (IGDR); 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 ); Sheffield Children's NHS Foundation Trust; CHU Clermont-Ferrand; CHU de Lille -; Genetic Health Services Victoria; Innsbruck Medical University = Medizinische Universität Innsbruck (IMU); University Hospitals Leicester; University of Melbourne; Victorian Clinical Genetics Services; University of Northern British Columbia Prince George (UNBC); Hamad Bin Khalifa University Doha, Qatar (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
نبذة مختصرة : International audience ; 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.
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