Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.

Original publication

DOI

10.1038/ng.3676

Type

Journal article

Journal

Nat Genet

Publication Date

11/2016

Volume

48

Pages

1349 - 1358

Keywords

Animals, Cells, Cultured, Endosomal Sorting Complexes Required for Transport, Female, Humans, Male, Mice, Mutation, Missense, Nedd4 Ubiquitin Protein Ligases, Periventricular Nodular Heterotopia, Protein Domains, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Ubiquitin, Ubiquitin-Protein Ligases