Solving the puzzle of protocadherin-19 mosaicism to understand the pathophysiology of PCDH19 Female Epilepsy (PCDH19-FE)

PCDH19 Female Epilepsy (PCDH19-FE) is a debilitating neurological condition characterized by early-onset seizures, intellectual disability and autism. The disease is caused by mutations in the X-chromosome gene PCDH19 that encodes protocadherin-19, whose function in the brain is largely unknown. PCDH19-FE is characterized by a peculiar inheritance pattern as it affects females, while spares transmitting males. To explain gender differences, a cellular interference model has been proposed but never proven: random chromosome X-inactivation in females leads to tissue mosaicism in which cells expressing wild-type PCDH19 and cells not expressing or expressing a mutant PCDH19 coexist. This tissue mosaicism is proposed to scramble cell-to-cell communication. We generated a PCDH19 conditional KO mouse that we will characterize from a morphological, functional and behavioral point of view in order to investigate PCDH19-FE etiology with a focus on tissue mosaicism. This research will return crucial molecular insights into the causes of PCDH19-FE at the levels of synapse, neuron and neuronal network, and will provide the fundamental bases necessary for the development of future treatments.