RESUMEN
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.
RESUMEN
The Reelin-DAB1 signaling pathway plays a crucial role in regulating neuronal migration and synapse function. Although many rare heterozygous variants in the Reelin gene (RELN) have been identified in patients with autism spectrum disorder (ASD), most variants are still of unknown clinical significance. Also, genetic data suggest that heterozygous variants in RELN alone appear to be insufficient to cause ASD. Here, we describe the identification and functional characterization of rare compound heterozygous missense variants in RELN in a patient with ASD in whom we have previously reported hyperfunctional mTORC1 signaling of yet unknown etiology. Using iPSC-derived neural progenitor cells (NPCs) from this patient, we provide experimental evidence that the identified variants are deleterious and lead to diminished Reelin secretion and impaired Reelin-DAB1 signal transduction. Also, our results suggest that mTORC1 pathway overactivation may function as a second hit event contributing to downregulation of the Reelin-DAB1 cascade in patient-derived NPCs, and that inhibition of mTORC1 by rapamycin attenuates Reelin-DAB1 signaling impairment. Taken together, our findings point to an abnormal interplay between Reelin-DAB1 and mTORC1 networks in nonsyndromic ASD.
