ArticleAmerican journal of human genetics2020
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.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 54 citations in OpenAlex.
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- The CCR4-NOT complex: a multifaceted sensor of molecular signals instructing eukaryotic mRNA translation and stability.Nucleic acids research · 2025Review
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- Using Whole Exome Sequencing to Identify Genetic Causes of Neurodevelopmental Disorders in a Cohort of 11 Patients: A Single Center Experience.International journal of molecular sciences · 2025Article
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Authors and funding
73 authors at 20 institutions in 10 countries.
Lisenka E L M VissersDepartment 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.
Sreehari KalvakuriDevelopment, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA.
Elke de BoerDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Sinje GeuerDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Machteld OudDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Inge van OutersterpDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Michael KwintDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Melde WitmondDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Simone KerstenDepartment 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.
Daniel L PollaDepartment 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.
Dilys WeijersDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Amber BegtrupGeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA.
Kirsty McWalterGeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA.
Anna RuizPaediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain.
Elisabeth GabauPaediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain.
Jenny E V MortonWest Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham Women's and Children's NHS Foundation Trust, Edgbaston B15 2TG, UK.
Christopher GriffithDepartment of Pediatrics, University of South Florida, Tampa, FL 33606, USA.
Karin WeissThe Genetics Institute, Rambam Health Care Center, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Candace GambleCook Children's, 801 7th Ave, Fort Worth, TX 76104, USA.
James BartleyPediatric Specialty Clinics, Loma Linda University, 11234 Anderson St., Loma Linda, CA 92354, USA.
Hilary J VernonDepartment of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Kendra BrunetPorcupine Health Unit, 169 Pine St S, Timmins, ON P4N 2K3, Canada.
Claudia RuivenkampDepartment of Clinical Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands.
Sarina G KantDepartment of Clinical Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands.
Paul KruszkaNational Human Genome Research Institute, National Institutes of Health, 10 Center Dr, Bethesda, MD 20814, USA.
Austin LarsonDepartment of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Alexandra AfenjarCRMR malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, Département de génétique, Sorbonne Université, AP-HP, Hôpital Trousseau, 75012 Paris, France.
Thierry Billette de VillemeurChildren's Hospital of San Antonio, 333 N Santa Rosa St, San Antonio, TX 78207, USA.
Kimberly NugentChildren's Hospital of San Antonio, 333 N Santa Rosa St, San Antonio, TX 78207, USA.
DDD StudyWellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
F Lucy RaymondDepartment of Medical Genetics, University of Cambridge, CB2 0XY Cambridge, UK.
Hanka VenselaarCenter for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (RIMLS), PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Florence DemurgerCentre Hospitalier Bretagne Atlantique, 20 Boulevard Général Maurice Guillaudot, BP 70555, 56017 Vannes Cedex, France.
Claudia Soler-AlfonsoDepartment of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Dong LiCenter for Applied Genomics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
Elizabeth BhojCenter for Applied Genomics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
Ian HayesGenetic Health Service New Zealand, 2 Park Road, Grafton, Auckland 1023, New Zealand.
Nina Powell HamiltonDepartment of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, 1522 Simpson Road East, Ann Arbor, MI 48109-5718, USA.
Ayesha AhmadDepartment of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, 1522 Simpson Road East, Ann Arbor, MI 48109-5718, USA.
Rachel FisherDepartment of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, 1522 Simpson Road East, Ann Arbor, MI 48109-5718, USA.
Myrthe van den BornDepartment for Clinical Genetics, Erasmus MC, Postbus 2040, 3000 CA Rotterdam, the Netherlands.
Marjolaine WillemsCentre Hospitalier Universitaire de Montpellier, 191 av. du Doyen Giraud, 34295 Montpellier Cedex 5, France.
Arthur SorlinINSERM 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.
Julian DelanneINSERM 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.
Sebastien MouttonINSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, 33401 Talence, France.
Philippe ChristopheINSERM 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.
Frederic Tran Mau-ThemINSERM 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.
Antonio VitobelloINSERM 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.
Himanshu GoelHunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW 2308, Australia.
Lauren MassinghamDivision of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI 02905, USA.
Chanika PhornphutkulDivision of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI 02905, USA.
Jennifer SchwabDivision of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI 02905, USA.
Boris KerenGenetic Department, APHP, Sorbonne Université, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
Perrine CharlesGenetic Department, APHP, Sorbonne Université, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
Maaike VreeburgDepartment of Clinical Genetics, Maastricht UMC+, Postbus 5800, 6202 AZ Maastricht, the Netherlands.
Lenika De SimoneUIC Pediatric Genetics, 840 South Wood Street, Chicago, IL 60612, USA.
George HogansonUIC Pediatric Genetics, 840 South Wood Street, Chicago, IL 60612, USA.
Maria IasconeLaboratorio di genetica Medica, ASST Papa Giovanni XXIII, Bergamo 24127, Italy.
Donatella MilaniFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Highly Intensive Care Unit, Milan, 20122, Italy.
Lucie EvenepoelCentre de Génétique Humaine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10-1200, Brussels, Belgium.
Nicole RevencuCentre de Génétique Humaine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10-1200, Brussels, Belgium.
D Isum WardSanford Health 1600 W. 22th St, Sioux Falls, SD 57105, USA.
Kaitlyn BurnsSanford Health 1600 W. 22th St, Sioux Falls, SD 57105, USA.
Ian KrantzThe Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
Sarah E RaibleThe Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
Jill R MurrellThe Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
Kathleen WoodThe Children's Hospital of Philadelphia, Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
Megan T ChoGeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA.
Hans van BokhovenDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Maximilian MuenkeThe Genetics Institute, Rambam Health Care Center, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Tjitske KleefstraDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Rolf BodmerDevelopment, 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.
Arjan P M de BrouwerDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Radboud University Nijmegen · NLChildren's Hospital of Philadelphia · USInserm · FRBrown University · USSorbonne Université · FRUniversity of Michigan · USChildren's Hospital of San Antonio · USCliniques Universitaires Saint-Luc · BELeiden University · NLSanford Burnham Prebys Medical Discovery Institute · USSanford Health · USTechnion – Israel Institute of Technology · ILUniversitat Autònoma de Barcelona · ESUniversity of Illinois Chicago · USBaylor College of Medicine · USBirmingham Women's Hospital · GBCentre hospitalier Bretagne Atlantique · FRCentre Hospitalier Universitaire de Montpellier · FRCook Children's Medical Center · USErasmus MC · NL
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
Indexed as
AllelesDevelopmental DisabilitiesFemaleGene ExpressionGenetic VariationHaploinsufficiencyHeterozygoteHumansMaleNervous System MalformationsNeurodevelopmental DisordersNuclear Receptor Subfamily 4, Group A, Member 2PhenotypeProtein StabilityReceptors, CCR4RNACCR4 protein, humanCNOT1 protein, humanNR4A2 protein, humanNuclear Receptor Subfamily 4, Group A, Member 2Receptors, CCR4RNATranscription FactorsCCR4-NOT complexCNOT1de novo mutationsdevelopmental delayDrosophilaexome sequencinggenomicsintellectual disabilityneurodevelopment
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