De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Autor:	Vissers LELM; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address: lisenka.vissers@radboudumc.nl., Kalvakuri S; Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA., de Boer E; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Geuer S; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Oud M; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., van Outersterp I; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Kwint M; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Witmond M; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Kersten S; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen the Netherlands., Polla DL; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; CAPES Foundation, Ministry of Education of Brazil, 70040-031 Brasília, Brazil., Weijers D; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Begtrup A; GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA., McWalter K; GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA., Ruiz A; Paediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain., Gabau E; Paediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain., Morton JEV; West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham Women's and Children's NHS Foundation Trust, Edgbaston B15 2TG, UK., Griffith C; Department of Pediatrics, University of South Florida, Tampa, FL 33606, USA., Weiss K; The Genetics Institute, Rambam Health Care Center, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel., Gamble C; Cook Children's, 801 7th Ave, Fort Worth, TX 76104, USA., Bartley J; Pediatric Specialty Clinics, Loma Linda University, 11234 Anderson St., Loma Linda, CA 92354, USA., Vernon HJ; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Brunet K; Porcupine Health Unit, 169 Pine St S, Timmins, ON P4N 2K3, Canada., Ruivenkamp C; Department of Clinical Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands., Kant SG; Department of Clinical Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands., Kruszka P; National Human Genome Research Institute, National Institutes of Health, 10 Center Dr, Bethesda, MD 20814, USA., Larson A; Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA., Afenjar A; CRMR malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, Département de génétique, Sorbonne Université, AP-HP, Hôpital Trousseau, 75012 Paris, France., Billette de Villemeur T; Children's Hospital of San Antonio, 333 N Santa Rosa St, San Antonio, TX 78207, USA., Nugent K; Children's Hospital of San Antonio, 333 N Santa Rosa St, San Antonio, TX 78207, USA., Raymond FL; Department of Medical Genetics, University of Cambridge, CB2 0XY Cambridge, UK., Venselaar H; Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (RIMLS), PO Box 9101, 6500 HB Nijmegen, the Netherlands., Demurger F; Centre Hospitalier Bretagne Atlantique, 20 Boulevard Général Maurice Guillaudot, BP 70555, 56017 Vannes Cedex, France., Soler-Alfonso C; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA., Li D; Center for Applied Genomics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA., Bhoj E; Center for Applied Genomics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA., Hayes I; Genetic Health Service New Zealand, 2 Park Road, Grafton, Auckland 1023, New Zealand., Hamilton NP; Department of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, 1522 Simpson Road East, Ann Arbor, MI 48109-5718, USA., Ahmad A; Department of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, 1522 Simpson Road East, Ann Arbor, MI 48109-5718, USA., Fisher R; Department of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, 1522 Simpson Road East, Ann Arbor, MI 48109-5718, USA., van den Born M; Department for Clinical Genetics, Erasmus MC, Postbus 2040, 3000 CA Rotterdam, the Netherlands., Willems M; Centre Hospitalier Universitaire de Montpellier, 191 av. du Doyen Giraud, 34295 Montpellier Cedex 5, France., Sorlin A; INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, 2 Boulevard du Maréchal de Lattre de Tassigny, 21000 Dijon, France., Delanne J; INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, 2 Boulevard du Maréchal de Lattre de Tassigny, 21000 Dijon, France., Moutton S; INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, 33401 Talence, France., Christophe P; INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; Laboratoire de génétique, Innovation en diagnostic génomique des maladies rares UF6254, Plateau Technique de Biologie, CHU Dijon, 14 rue Paul Gaffarel, BP 77908, 21079 Dijon, France., Mau-Them FT; INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; Laboratoire de génétique, Innovation en diagnostic génomique des maladies rares UF6254, Plateau Technique de Biologie, CHU Dijon, 14 rue Paul Gaffarel, BP 77908, 21079 Dijon, France., Vitobello A; INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; Laboratoire de génétique, Innovation en diagnostic génomique des maladies rares UF6254, Plateau Technique de Biologie, CHU Dijon, 14 rue Paul Gaffarel, BP 77908, 21079 Dijon, France., Goel H; Hunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW 2308, Australia., Massingham L; Division of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI 02905, USA., Phornphutkul C; Division of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI 02905, USA., Schwab J; Division of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI 02905, USA., Keren B; Genetic Department, APHP, Sorbonne Université, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France., Charles P; Genetic Department, APHP, Sorbonne Université, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France., Vreeburg M; Department of Clinical Genetics, Maastricht UMC+, Postbus 5800, 6202 AZ Maastricht, the Netherlands., De Simone L; UIC Pediatric Genetics, 840 South Wood Street, Chicago, IL 60612, USA., Hoganson G; UIC Pediatric Genetics, 840 South Wood Street, Chicago, IL 60612, USA., Iascone M; Laboratorio di genetica Medica, ASST Papa Giovanni XXIII, Bergamo 24127, Italy., Milani D; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Highly Intensive Care Unit, Milan, 20122, Italy., Evenepoel L; Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10-1200, Brussels, Belgium., Revencu N; Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10-1200, Brussels, Belgium., Ward DI; Sanford Health 1600 W. 22th St, Sioux Falls, SD 57105, USA., Burns K; Sanford Health 1600 W. 22th St, Sioux Falls, SD 57105, USA., Krantz I; The Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA., Raible SE; The Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA., Murrell JR; The Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA., Wood K; The Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA., Cho MT; GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA., van Bokhoven H; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Muenke M; The Genetics Institute, Rambam Health Care Center, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel., Kleefstra T; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands., Bodmer R; Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA. Electronic address: rolf@sbpdiscovery.org., de Brouwer APM; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2020 Jul 02; Vol. 107 (1), pp. 164-172. Date of Electronic Publication: 2020 Jun 17.
DOI:	10.1016/j.ajhg.2020.05.017
Abstrakt:	CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development. (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
Databáze:	MEDLINE
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