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The genetic cause of periventricular nodular heterotopia (PNH) resulting in neurodevelopmental disorders remains in many cases unknown. Broix and colleagues showed 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 developmental delay. PNH-associated mutants were sensitive to proteasome degradation. Moreover, in utero electroporation studies showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Finally, the authors showed that excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations were associated with deregulation of mTORC1 and AKT activities.

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Posted by Nicola Brunetti-Pierri