Calcium-calmodulin dependent protein kinase type II (CAMK2) is among the most extensively studied proteins in the brain, shown to be critically important for synaptic plasticity, learning and memory formation. Impaired CAMK2 signaling has been implicated in multiple neurological disorders, including Angelman Syndrome, Fragile X and Alzheimer’s disease. In collaboration with other labs using whole-exome sequencing in children with neurodevelopmental disorders, our lab recently identified a multitude of de novo missense mutations in CAMK2, indicating that mutations in the CAMK2 genes themselves can cause neurodevelopmental disorders. However, how the identified missense mutations cause dysfunction of CAMK2, its down-stream signaling pathways and ultimately neurodevelopment is largely unknown, since most of our knowledge of CAMK2 neurobiology has focused on the function of CAMK2 in the adult brain.
Our lab aims to investigate the function of CAMK2 in neurodevelopment and its role in neurodevelopmental disorders, using a multidisciplinary approach of molecular biology, electrophysiology and behavior. Additionally, our lab will make use of the exciting novel iPSC technology combined with the CRISPR/Cas9 technique, to study the effect of the CAMK2 mutations on human neurons. Taken together, these findings will provide new insights in the fundamental CAMK2 signaling processes that underlie normal brain development, and will lead to a better comprehension of how CAMK2 is involved in the etiology of neurodevelopmental disorders. Finally, making use of the functional genomics screen we have been developing together with the Elgersma lab in the last years, PRiSM (Pipeline of Rapid in vivo and in vitro Screening of Mutations), functional genomics.nl we aim to create a platform for functional genomics studies to assess the pathogenicity of mutations identified in CAMK2 and its down-stream effectors in individuals with a neurodevelopmental disorder.