Mutations in the HECT domain of NEDD4L lead to AKT–mTOR pathway deregulation and cause periventricular nodular heterotopia - Archive ouverte HAL Access content directly
Journal Articles Nature Genetics Year : 2016

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

Karine Poirier
  • Function : Author
Yoann Saillour
  • Function : Author
Nicolas Lebrun
  • Function : Author
  • PersonId : 1326826
Giuseppe Muraca
  • Function : Author
Anne Boland
Robert Olaso
Laurent Nguyen
Jean-François Deleuze
  • Function : Author
  • PersonId : 1015006

Abstract

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.
Fichier principal
Vignette du fichier
emss-69768.pdf (2.65 Mo) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

hal-02371039 , version 1 (18-06-2024)

Identifiers

Cite

Loic Broix, Hélène Jagline, Ekaterina L Ivanova, Stéphane Schmucker, Nathalie Drouot, et al.. Mutations in the HECT domain of NEDD4L lead to AKT–mTOR pathway deregulation and cause periventricular nodular heterotopia. Nature Genetics, 2016, 48 (11), pp.1349-1358. ⟨10.1038/ng.3676⟩. ⟨hal-02371039⟩
220 View
0 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More