ERA-Net E-Rare

Molecular and cellular neurobiologists, biochemists, clinicians and bioinformaticians will together investigate causes and consequences of neuron mis-positioning (heterotopia) within the cerebral cortex. These are a set of rare developmental disorders which lead to severe epilepsy and intellectual disability. Our data suggest these disorders may form a spectrum ranging from abnormal neuron clusters at the cerebral ventricles (periventricular), to heterotopias embedded in the white matter (subcortical). To investigate the converging and specific pathways underlying these disorders, it is critical to understand the abnormally functioning cell types and developmental trajectories, as well as the functional endpoints. Combining mouse and human cell mutant models selected to represent archetypical heterotopia situations, we will use a multi-omics approach to decipher the disrupted cell-type specific, dynamic transcriptional and biochemical pathways. Our aims are to compare: 1) perturbed gene and protein networks; 2) cellular and circuit dysfunctions; and 3) clinical and genetic features. Workpackages will converge to pinpoint overlapping and/or specific molecular, cellular and physiological signatures, clarifying causes and consequences. This project will harmonize data, expanding upon an existing bioinformatics platform, ECTOPIA-DB, which will allow multi-dimensional data integration, aiding the identification of new candidate genes and potential drug targets. Families will benefit from improved stratification and diagnosis, and this project will provide knowledge of causality.