@ARTICLE{10.3389/fncel.2021.803302, AUTHOR={Moreira, Danielle de Paula and Suzuki, Angela May and Silva, André Luiz Teles e and Varella-Branco, Elisa and Meneghetti, Maria Cecília Zorél and Kobayashi, Gerson Shigeru and Fogo, Mariana and Ferrari, Merari de Fátima Ramires and Cardoso, Rafaela Regina and Lourenço, Naila Cristina Vilaça and Griesi-Oliveira, Karina and Zachi, Elaine Cristina and Bertola, Débora Romeo and Weinmann, Karina de Souza and Lima, Marcelo Andrade de and Nader, Helena Bonciani and Sertié, Andrea Laurato and Passos-Bueno, Maria Rita}, TITLE={Neuroprogenitor Cells From Patients With TBCK Encephalopathy Suggest Deregulation of Early Secretory Vesicle Transport}, JOURNAL={Frontiers in Cellular Neuroscience}, VOLUME={15}, YEAR={2022}, URL={https://www.frontiersin.org/articles/10.3389/fncel.2021.803302}, DOI={10.3389/fncel.2021.803302}, ISSN={1662-5102}, ABSTRACT={Biallelic pathogenic variants in TBCK cause encephaloneuropathy, infantile hypotonia with psychomotor retardation, and characteristic facies 3 (IHPRF3). The molecular mechanisms underlying its neuronal phenotype are largely unexplored. In this study, we reported two sisters, who harbored biallelic variants in TBCK and met diagnostic criteria for IHPRF3. We provided evidence that TBCK may play an important role in the early secretory pathway in neuroprogenitor cells (iNPC) differentiated from induced pluripotent stem cells (iPSC). Lack of functional TBCK protein in iNPC is associated with impaired endoplasmic reticulum-to-Golgi vesicle transport and autophagosome biogenesis, as well as altered cell cycle progression and severe impairment in the capacity of migration. Alteration in these processes, which are crucial for neurogenesis, neuronal migration, and cytoarchitecture organization, may represent an important causative mechanism of both neurodevelopmental and neurodegenerative phenotypes observed in IHPRF3. Whether reduced mechanistic target of rapamycin (mTOR) signaling is secondary to impaired TBCK function over other secretory transport regulators still needs further investigation.} }