Gene Interaction Networks

Disturbances in brain development can cause neurodevelopmental disorders such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID). Although a strong genetic component in the genesis of these disorders is evident, identification of causal defects is complicated by the vast number of genes involved. A growing body of evidence supports the relatedness of these disorders on phenotypic and genetic level and it is now known that distinct neurodevelopmental disorders can be genetically congruent. In other words, a specific dysfunction of the same gene or biological pathway may underlie distinct clinical outcomes. Recently we identified two mutations in ANK3, encoding for the AnkyrinG protein which has a key role in a network of proteins in the nodes of Ranvier and the axon initial segment. We found a mutation completely disabling AnkyrinG function, leading to ID and severe behavioural problems. Another mutation that partially diminished AnkyrinG function caused ASD, ADHD and learning difficulties. Others described that variants in ANK3 are associated with bipolar disorder and schizophrenia. We hypothesize that variants in ANK3 and its interactors can cause a wide range of neurodevelopmental disorders, depending on the nature of the variant. We will use this AnkyrinG protein network as a working model to unravel how variants in single genes can cause distinct clinical outcomes. Using state-of-the art techniques such as targeted next-generation sequencing, induced neuronal cell generation and animal models, we aim to get novel insights into the ‘many genes, common pathways’ paradigm of today’s clinical genetics.

ANK3 network