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

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

1 University of Manchester [Manchester]
2 Regional Genetic Service, St Mary's Hospital, Manchester
3 East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital
4 Mendel Laboratory
5 Center for Medical Genetics [Ghent]
6 CRG - Centre for Genomic Regulation [Barcelona]
7 Guy's Hospital [London]
8 Centre for Human Genetics
9 IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
10 Nottingham City Hospital
11 Western Sydney University
12 UBC - University of British Columbia
13 Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow)
14 University of Edinburgh
15 Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes]
16 Department of Clinical Genetics
17 CLAD Ouest
18 IGDR - Institut de Génétique et Développement de Rennes
19 Sheffield Children's NHS Foundation Trust
20 CHU Clermont-Ferrand
21 CHU de Lille
22 Genetic Health Services Victoria
23 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
24 University Hospitals Leicester
25 University of Melbourne
26 Victorian Clinical Genetics Services
27 UNBC - University of Northern British Columbia [Prince George]
28 HBKU - Hamad Bin Khalifa University
29 The Wellcome Trust Sanger Institute [Cambridge]

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: Abnormalities; Multiple; ACTB; Actins; Adolescent; Adult; Aged; Animals; Cell Cycle; Cell Proliferation; Child; Preschool; chromatin; Codon; Nonsense; Coloboma; Developmental Disabilities; developmental disorder; Facies; Female; Frameshift Mutation; Gene Deletion; Haploinsufficiency; Humans; Infant; Newborn; Intellectual Disability; Male; malformations; Malformations of Cortical Development; Mice; RNA Interference; RNA; Small Interfering; Young Adult; β-actin

Domains: Life Sciences [q-bio]; Genetics

Sara Cuvertino, Helen M. Stuart, Kate E. Chandler, Neil A. Roberts, Ruth Armstrong, et al.. ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder. American Journal of Human Genetics, 2017, 101 (6), pp.1021-1033. ⟨10.1016/j.ajhg.2017.11.006⟩. ⟨hal-01699166⟩