Mutations in the HECT domain of NEDD4L lead to AKT/mTOR pathway deregulation and cause periventricular nodular heterotopia

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in the HECT domain of the E3 ubiquitin ligase NEDD4L lead to PNH associated with toes syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed a sensitivity of PNH-associated mutants to proteasome degradation. Moreover, in utero electroporation approach showed that PNH-related mutants and excess of wild type (WT) NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin based experiments, revealed differential deregulation of pathways involved. Excess of WT NEDD4L leads to a disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with a deregulation of mTORC1 and AKT activities. Altogether, these data provide insights to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.