AUTHOR=Moreira Danielle de Paula , Suzuki Angela May , Silva André Luiz Teles e , Varella-Branco Elisa , Meneghetti Maria Cecília Zorél , Kobayashi Gerson Shigeru , Fogo Mariana , Ferrari Merari de Fátima Ramires , Cardoso Rafaela Regina , Lourenço Naila Cristina Vilaça , Griesi-Oliveira Karina , Zachi Elaine Cristina , Bertola Débora Romeo , Weinmann Karina de Souza , Lima Marcelo Andrade de , Nader Helena Bonciani , Sertié Andrea Laurato , 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/journals/cellular-neuroscience/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.