De novo missense mutation in CERS6 identified in a patient with subcortical heterotopia

A de novo missense mutation in ceramide synthase 6 (CERS6) was identified by human exome sequencing in a patient with 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. Ceramide synthases are important for the biogenesis of ceramides in the endoplasmic reticulum and mitochondria. These are then transferred to the Golgi apparatus for the formation of complex sphingolipids, and in this form further transported to other cell membranes. The major aim of this project is to understand the role of ceramide synthases in cortical development, a highly understudied area. Knockdown and overexpression approaches are being used. Importantly, we will question the impact of CERS6 patient-specific mutationsin the processes mentioned above, helping to explain the formation of heterotopia. Our analyses suggest delayed migration of neurons, disturbance of the apical surface and decreased proliferation of late radial glial progenitors upon CerS6 knockdown in mouse cortex. Preliminary analyses of overexpression studies indicate increased accumulation of Tbr2+ basal progenitors in the ventricular zone. Our ongoing and future experiments are aimed at identifying further mutations, and exploring the subcellular mechanisms impacted by normal and mutant CERS6. These studies highlight the important and little-known roles played by lipid biogenesis factors in cortical development.