Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18372
Title: De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.
Authors: Küry, Sébastien;van Woerden, Geeske M;Besnard, Thomas;Proietti Onori, Martina;Latypova, Xénia;Towne, Meghan C;Cho, Megan T;Prescott, Trine E;Ploeg, Melissa A;Sanders, Stephan;Stessman, Holly A F;Isidor, Bertrand;Pasquier, Laurent;Redon, Richard;Yang, Yaping;State, Matthew W;Kleefstra, Tjitske;Cogné, Benjamin;Petrovski, Slavé;Retterer, Kyle;Eichler, Evan E;Rosenfeld, Jill A;Agrawal, Pankaj B;Bézieau, Stéphane;Odent, Sylvie;Elgersma, Ype;Mercier, Sandra;Pujol, Aurora;Distel, Ben;Robak, Laurie A;Bernstein, Jonathan A;Denommé-Pichon, Anne-Sophie;Lesca, Gaëtan;Sellars, Elizabeth A;Berg, Jonathan;Carré, Wilfrid;Busk, Øyvind Løvold;van Bon, Bregje W M;Waugh, Jeff L;Deardorff, Matthew;Hoganson, George E;Bosanko, Katherine B;Johnson, Diana S;Dabir, Tabib;Holla, Øystein Lunde;Sarkar, Ajoy;Tveten, Kristian;de Bellescize, Julitta;Braathen, Geir J;Terhal, Paulien A;Grange, Dorothy K;van Haeringen, Arie;Lam, Christina;Mirzaa, Ghayda;Burton, Jennifer;Bhoj, Elizabeth J;Douglas, Jessica;Santani, Avni B;Nesbitt, Addie I;Helbig, Katherine L;Andrews, Marisa V;Begtrup, Amber;Tang, Sha;van Gassen, Koen L I;Juusola, Jane;Foss, Kimberly;Enns, Gregory M;Moog, Ute;Hinderhofer, Katrin;Paramasivam, Nagarajan;Lincoln, Sharyn;Kusako, Brandon H;Lindenbaum, Pierre;Charpentier, Eric;Nowak, Catherine B;Cherot, Elouan;Simonet, Thomas;Ruivenkamp, Claudia A L;Hahn, Sihoun;Brownstein, Catherine A;Xia, Fan;Schmitt, Sébastien;Deb, Wallid;Bonneau, Dominique;Nizon, Mathilde;Quinquis, Delphine;Chelly, Jamel;Rudolf, Gabrielle;Sanlaville, Damien;Parent, Philippe;Gilbert-Dussardier, Brigitte;Toutain, Annick;Sutton, Vernon R;Thies, Jenny;Peart-Vissers, Lisenka E L M;Boisseau, Pierre;Vincent, Marie;Grabrucker, Andreas M;Dubourg, Christèle;Tan, Wen-Hann;Verbeek, Nienke E;Granzow, Martin;Santen, Gijs W E;Shendure, Jay
Affiliation: Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Department of Medicine, The University of Melbourne,Royal Melbourne Hospital, Melbourne, VIC 3010, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherland
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
CRCINA, Inserm, Université d'Angers, Université de Nantes, 44000 Nantes, France
Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
GeneDx, Gaithersburg, MD 20877, USA
Department of Neuroscience, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Department of Pharmacology, Creighton University Medical School, Omaha, NE 68178, USA
Neurometabolic Diseases Laboratory, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908 Barcelona, and CIBERER U759, Center for Biomedical Research on Rare Diseases, 08908 Barcelona, Spain
Catalan Institution of Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Service de génétique, Centre de Référence des Anomalies du Développement, Hospices Civils de Lyon, 69288 Lyon, France
INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, 69675 Bron, France
Section of Genetics and Metabolism, Arkansas Children's Hospital, Little Rock, AR 72202, USA
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
Department of Human Genetics, Nijmegen Center for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, the Netherlands
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
Department of Pediatrics, Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Pediatrics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK
Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK
Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK
Epilepsy, Sleep and Pediatric Neurophysiology Department, Hospices Civils, Lyon, 69677 Bron, France
Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway
Department of Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO 63110, USA
Department of Clinical Genetics, Leiden University Medical Center (LUMC), 2333 ZA Leiden, the Netherlands
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA 98105, USA
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Division of Genomic Diagnostics, Department of Path and Lab Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Path and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4238, USA
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Division of Clinical Genomics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA
Institute of Human Genetics, University Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
Laboratoire de Génétique Moléculaire & Génomique, CHU de Rennes, 35033 Rennes, France
CHU Angers, Département de Biochimie et Génétique, 49933 Angers Cedex 9, France
UMR INSERM 1083 - CNRS 6015, 49933 Angers Cedex 9, France
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, 67091 Strasbourg, France
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404 Illkirch, France
Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67000 Strasbourg, France
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404 Illkirch, France
Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098 Strasbourg Cedex, France
CHRU Brest, Génétique médicale, 29609 Brest, France
CHU Poitiers, Service de Génétique, BP577, 86021 Poitiers, France
EA 3808 Université Poitiers, France
CHU Tours, Service de Génétique, 2 Boulevard Tonnellé, 37044 Tours, France
Baylor Genetics, Houston, TX 77030, USA
Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA 98105, USA
CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Department of Biological Sciences, University of Limerick, Limerick V94 T9PX, Ireland
Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
Howard Hughes Medical Institute, Seattle, WA 98195, USA
CHU Rennes, Service de Génétique Clinique, CNRS UMR6290, Université Rennes1, 35203 Rennes, France
INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France
CHU Nantes, l'institut du thorax, 44093 Nantes, France
Department of Human Genetics, Nijmegen Center for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, the Netherlands
Réseau de génétique et génomique médicale - Hôpitaux Universitaires du Grand Ouest, CHU Rennes, Service de Génétique Clinique, 35203 Rennes, France
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Issue Date: 2-Nov-2017
Citation: American journal of human genetics 2017; 101(5): 768-788
Abstract: Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18372
DOI: 10.1016/j.ajhg.2017.10.003
ORCID: 0000-0002-1527-961X
PubMed URL: 29100089
Type: Journal Article
Subjects: AMPAR
CAMK2
CAMK2A
CAMK2B
NMDAR
de novo mutations
intellectual disability
synaptic plasticity
Appears in Collections:Journal articles

Files in This Item:
There are no files associated with this item.


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.