De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

  • Am J Hum Genet. 2017 Nov 2;101(5):768-788. doi: 10.1016/j.ajhg.2017.10.003.
Sébastien Küry  1 ,  Geeske M van Woerden  2 ,  Thomas Besnard  3 ,  Martina Proietti Onori  2 ,  Xénia Latypova  3 ,  Meghan C Towne  4 ,  Megan T Cho  5 ,  Trine E Prescott  6 ,  Melissa A Ploeg  2 ,  Stephan Sanders  7 ,  Holly A F Stessman  8 ,  Aurora Pujol  9 ,  Ben Distel  10 ,  Laurie A Robak  11 ,  Jonathan A Bernstein  12 ,  Anne-Sophie Denommé-Pichon  13 ,  Gaëtan Lesca  14 ,  Elizabeth A Sellars  15 ,  Jonathan Berg  16 ,  Wilfrid Carré  17 ,  Øyvind Løvold Busk  6 ,  Bregje W M van Bon  18 ,  Jeff L Waugh  19 ,  Matthew Deardorff  20 ,  George E Hoganson  21 ,  Katherine B Bosanko  15 ,  Diana S Johnson  22 ,  Tabib Dabir  23 ,  Øystein Lunde Holla  6 ,  Ajoy Sarkar  24 ,  Kristian Tveten  6 ,  Julitta de Bellescize  25 ,  Geir J Braathen  6 ,  Paulien A Terhal  26 ,  Dorothy K Grange  27 ,  Arie van Haeringen  28 ,  Christina Lam  29 ,  Ghayda Mirzaa  30 ,  Jennifer Burton  21 ,  Elizabeth J Bhoj  31 ,  Jessica Douglas  32 ,  Avni B Santani  33 ,  Addie I Nesbitt  34 ,  Katherine L Helbig  35 ,  Marisa V Andrews  27 ,  Amber Begtrup  5 ,  Sha Tang  36 ,  Koen L I van Gassen  26 ,  Jane Juusola  5 ,  Kimberly Foss  37 ,  Gregory M Enns  12 ,  Ute Moog  38 ,  Katrin Hinderhofer  38 ,  Nagarajan Paramasivam  39 ,  Sharyn Lincoln  32 ,  Brandon H Kusako  32 ,  Pierre Lindenbaum  40 ,  Eric Charpentier  40 ,  Catherine B Nowak  32 ,  Elouan Cherot  17 ,  Thomas Simonet  25 ,  Claudia A L Ruivenkamp  28 ,  Sihoun Hahn  29 ,  Catherine A Brownstein  4 ,  Fan Xia  41 ,  Sébastien Schmitt  3 ,  Wallid Deb  3 ,  Dominique Bonneau  13 ,  Mathilde Nizon  3 ,  Delphine Quinquis  3 ,  Jamel Chelly  42 ,  Gabrielle Rudolf  43 ,  Damien Sanlaville  14 ,  Philippe Parent  44 ,  Brigitte Gilbert-Dussardier  45 ,  Annick Toutain  46 ,  Vernon R Sutton  47 ,  Jenny Thies  48 ,  Lisenka E L M Peart-Vissers  18 ,  Pierre Boisseau  3 ,  Marie Vincent  3 ,  Andreas M Grabrucker  49 ,  Christèle Dubourg  17 ,  Undiagnosed Diseases Network ,  Wen-Hann Tan  32 ,  Nienke E Verbeek  26 ,  Martin Granzow  38 ,  Gijs W E Santen  28 ,  Jay Shendure  50 ,  Bertrand Isidor  3 ,  Laurent Pasquier  51 ,  Richard Redon  40 ,  Yaping Yang  41 ,  Matthew W State  7 ,  Tjitske Kleefstra  18 ,  Benjamin Cogné  3 ,  GEM HUGO  52 ,  Deciphering Developmental Disorders Study  53 ,  Slavé Petrovski  54 ,  Kyle Retterer  5 ,  Evan E Eichler  50 ,  Jill A Rosenfeld  11 ,  Pankaj B Agrawal  55 ,  Stéphane Bézieau  56 ,  Sylvie Odent  51 ,  Ype Elgersma  57 ,  Sandra Mercier  3
Affiliations
  • 1. CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France. Electronic address: [email protected].
  • 2. Department of Neuroscience, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
  • 3. CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
  • 4. Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 5. GeneDx, Gaithersburg, MD 20877, USA.
  • 6. Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
  • 7. Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 8. 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.
  • 9. 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.
  • 10. Department of Neuroscience, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; 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.
  • 11. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 12. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 13. CHU Angers, Département de Biochimie et Génétique, 49933 Angers Cedex 9, France; UMR INSERM 1083 - CNRS 6015, 49933 Angers Cedex 9, France.
  • 14. 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.
  • 15. Section of Genetics and Metabolism, Arkansas Children's Hospital, Little Rock, AR 72202, USA.
  • 16. Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
  • 17. Laboratoire de Génétique Moléculaire & Génomique, CHU de Rennes, 35033 Rennes, France.
  • 18. 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.
  • 19. Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 20. Department of Pediatrics, Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 21. Department of Pediatrics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  • 22. Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
  • 23. Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK.
  • 24. Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.
  • 25. Epilepsy, Sleep and Pediatric Neurophysiology Department, Hospices Civils, Lyon, 69677 Bron, France.
  • 26. Department of Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
  • 27. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 28. Department of Clinical Genetics, Leiden University Medical Center (LUMC), 2333 ZA Leiden, the Netherlands.
  • 29. Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 30. Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA 98105, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 31. 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.
  • 32. Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 33. 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.
  • 34. Division of Genomic Diagnostics, Department of Path and Lab Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 35. Division of Clinical Genomics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 36. Division of Clinical Genomics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA.
  • 37. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 38. Institute of Human Genetics, University Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
  • 39. Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany and Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  • 40. INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France; CHU Nantes, l'institut du thorax, 44093 Nantes, France.
  • 41. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77030, USA.
  • 42. Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, 67091 Strasbourg, 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.
  • 43. 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.
  • 44. CHRU Brest, Génétique médicale, 29609 Brest, France.
  • 45. CHU Poitiers, Service de Génétique, BP577, 86021 Poitiers, France; EA 3808 Université Poitiers, France.
  • 46. CHU Tours, Service de Génétique, 2 Boulevard Tonnellé, 37044 Tours, France.
  • 47. Baylor Genetics, Houston, TX 77030, USA.
  • 48. Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 49. Department of Biological Sciences, University of Limerick, Limerick V94 T9PX, Ireland; Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland.
  • 50. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • 51. CHU Rennes, Service de Génétique Clinique, CNRS UMR6290, Université Rennes1, 35203 Rennes, France.
  • 52. Réseau de génétique et génomique médicale - Hôpitaux Universitaires du Grand Ouest, CHU Rennes, Service de Génétique Clinique, 35203 Rennes, France.
  • 53. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
  • 54. Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC 3010, Australia.
  • 55. Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 56. CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France; CRCINA, Inserm, Université d'Angers, Université de Nantes, 44000 Nantes, France.
  • 57. Department of Neuroscience, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands. Electronic address: [email protected].
PMID: 29100089 DOI: 10.1016/j.ajhg.2017.10.003
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.

Keywords
AMPAR; CAMK2; CAMK2A; CAMK2B; NMDAR; de novo mutations; intellectual disability; synaptic plasticity.