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

Sébastien Küry (Lead / Corresponding author), Geeske M. van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C. Towne, Megan T. Cho, Trine E. Prescott, Melissa A. Ploeg, Stephan J. Sanders, Holly A. F. Stessman, Aurora Pujol, Ben Distel, Laurie A. Robak, Jonathan A. Bernstein, Anne-Sophie Denommé-Pichon, Gaëtan Lesca, Elizabeth A. Sellars, Jonathan Berg, Wilfrid CarréØyvind Løvold Busk, Bregje W. M. van Bon, Jeff L. Waugh, Matthew Deardorff, George E. Hoganson, Katherine B. Bosanko, Diana S. Johnson, Tabib Dabir, Øystein Lunde Holla, Ajoy Sarkar, Kristian Tveten, Julitta de Bellescize, Geir J. Braathen, Paulien A. Terhal, Dorothy K. Grange, Arie van Haeringen, Christina Lam, Ghayda Mirzaa, Jennifer Burton, Elizabeth J. Bhoj, Jessica Douglas, Avni B. Santani, Addie I. Nesbitt, Katherine L. Helbig, Marisa V. Andrews, Amber Begtrup, Sha Tang, Koen L. I. van Gassen, Jane Juusola, Kimberly Foss, Undiagnosed Diseases Network, GEM HUGO, Deciphering Developmental Disorders (DDD) Study, Ype Elgersma

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)768-788
Number of pages21
JournalAmerican Journal of Human Genetics
Volume101
Issue number5
Early online date2 Nov 2017
DOIs
Publication statusPublished - 2 Nov 2017

Keywords

  • intellectual disability
  • synaptic plasticity
  • CAMK2
  • CAMK2A
  • CAMK2B
  • de novo mutations
  • NMDAR
  • AMPAR

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    Küry, S., van Woerden, G. M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M. C., Cho, M. T., Prescott, T. E., Ploeg, M. A., Sanders, S. J., Stessman, H. A. F., Pujol, A., Distel, B., Robak, L. A., Bernstein, J. A., Denommé-Pichon, A-S., Lesca, G., Sellars, E. A., Berg, J., ... Elgersma, Y. (2017). De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. American Journal of Human Genetics, 101(5), 768-788. https://doi.org/10.1016/j.ajhg.2017.10.003