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


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.

SUBMITTER: Broix L 

PROVIDER: S-EPMC5086093 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Broix Loïc L   Jagline Hélène H   Ivanova Ekaterina E   Schmucker Stéphane S   Drouot Nathalie N   Clayton-Smith Jill J   Pagnamenta Alistair T AT   Metcalfe Kay A KA   Isidor Bertrand B   Louvier Ulrike Walther UW   Poduri Annapurna A   Taylor Jenny C JC   Tilly Peggy P   Poirier Karine K   Saillour Yoann Y   Lebrun Nicolas N   Stemmelen Tristan T   Rudolf Gabrielle G   Muraca Giuseppe G   Saintpierre Benjamin B   Elmorjani Adrienne A   Moïse Martin M   Weirauch Nathalie Bednarek NB   Guerrini Renzo R   Boland Anne A   Olaso Robert R   Masson Cecile C   Tripathy Ratna R   Keays David D   Beldjord Cherif C   Nguyen Laurent L   Godin Juliette J   Kini Usha U   Nischké Patrick P   Deleuze Jean-François JF   Bahi-Buisson Nadia N   Sumara Izabela I   Hinckelmann Maria-Victoria MV   Chelly Jamel J  

Nature genetics 20161003 11


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 a  ...[more]

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