Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease
| Autor: | Yuji Nakamura, Naomi Tsuchida, Yoshiyuki Takahashi, Shinji Saitoh, Kohji Kato, Naomichi Matsumoto |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Immunofluorescence Regulator Developmental Signaling mTORC1 Biochemistry Neurological Signaling 0302 clinical medicine Cell Signaling Loss of Function Mutation Medicine and Health Sciences Post-Translational Modification Phosphorylation Multidisciplinary Hyperactivation Kinase Neurology Child Preschool Amino Acid Analysis Medicine Female Cellular Structures and Organelles Signal transduction Signal Transduction Research Article Science Immunoblotting Molecular Probe Techniques Nerve Tissue Proteins Mechanistic Target of Rapamycin Complex 1 Biology Research and Analysis Methods Cell Line 03 medical and health sciences Humans Molecular Biology Techniques Immunoassays Molecular Biology Alleles PI3K/AKT/mTOR pathway Loss function Molecular Biology Assays and Analysis Techniques Epilepsy Biology and Life Sciences Proteins Cell Biology 030104 developmental biology Neurodevelopmental Disorders Immunologic Techniques Cancer research Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 8, p e0221482 (2019) |
| ISSN: | 1932-6203 |
| Popis: | There have been increasing number of reports of SZT2-related neurological diseases, the main symptoms of which are epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum. SZT2 functions as a regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling in cultured human cell lines and mouse tissues. However, it remains to be determined whether mutations in SZT2 in human patients alter mTORC1 signaling. In this study, we aimed to investigate the functional consequence of biallelic SZT2 variants in Epstein-Barr virus-induced lymphoblastoid cell lines (LCLs) established from two patients with a typical SZT2-related neurodevelopmental disease. Increased phosphorylation of S6 kinase and S6 was identified in patient-derived cell lines under amino acid-starved condition, suggestive of constitutive hyperactivation of mTORC1 signaling. This result was validated by constitutive lysosomal localization of mTOR in patients' LCLs. Furthermore, patients' LCLs display an excessive response to slight amino acid stimulation. Our data suggest the loss-of-function nature of SZT2 mutations in the patients, and consequent hyperactivation of mTORC1 signaling in response to both amino acid starvation and stimulation in their LCLs. By these functional analyses, the pathogenicity of newly identified SZT2 variants can be determined, allowing for more detailed characterization of genotype-phenotype correlations. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|