DE NOVO MISSENSE MUTATION IN CERS6 IDENTIFIED IN A PATIENT WITH CORTICAL HETEROTOPIA

CHINNAPPA, K*; ROMERO, D. M.*; UZQUIANO, A; POIRIER, K; CIFUENTES-DIAZ, C; OLASO, R; DELEUZE, J.F.; BAHI-BUISSON, N; FRANCIS, F

Paris

Congreso; The FENS Forum of Neuroscience; 2022

A de novo missense mutation in CERS6 has been identified by human exome sequencing in a patientwith subcortical heterotopia. This is a rare disorder associated with epilepsy and intellectual disability,which may be caused by disturbances in cortical progenitors and /or migrating neurons. Ceramidesynthases are important for the biogenesis of ceramides in the endoplasmic reticulum, which will thenbe transported to the Golgi apparatus for the formation of complex sphingolipids to be transported tothe membranes. The major aim of this project is to understand the role of ceramide synthases innormal cortical development, for which we use knockdown and overexpression approaches.Importantly, we will question the impact of the CERS6 patient-specific mutation in the processesmentioned above leading to the formation of heterotopia. Our preliminary analyses suggest delayedmigration of neurons upon CerS6 knockdown in mouse cortex. Future experiments will continue lossof function experiments and phenotypic analyses. Furthermore, our future experiments will be aimedat understanding the subcellular mechanisms impacted by normal and mutant CerS6. These studieshighlight the understudied role played by lipid biogenesis factors in cortical development.