A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids.
Biochim Biophys Acta Mol Basis Dis
; 1870(6): 167232, 2024 08.
Article
in En
| MEDLINE
| ID: mdl-38759814
ABSTRACT
Focal malformations of cortical development (FMCDs) are brain disorders mainly caused by hyperactive mTOR signaling due to both inactivating and activating mutations of genes in the PI3K-AKT-mTOR pathway. Among them, mosaic and somatic activating mutations of the mTOR pathway activators are more frequently linked to severe form of FMCDs. A human stem cell-based FMCDs model to study these activating mutations is still lacking. Herein, we genetically engineer human embryonic stem cell lines carrying these activating mutations to generate cortical organoids. Mosaic and somatic expression of AKT3 activating mutations in cortical organoids mimicking the disease presentation with overproliferation and the formation of dysmorphic neurons. In parallel comparison of various AKT3 activating mutations reveals that stronger mutation is associated with more severe neuronal migratory and overgrowth defects. Together, we have established a feasible human stem cell-based model for FMCDs that could help to better understand pathogenic mechanism and develop novel therapeutic strategy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Organoids
/
Proto-Oncogene Proteins c-akt
/
Malformations of Cortical Development
Limits:
Humans
Language:
En
Journal:
Biochim Biophys Acta Mol Basis Dis
/
Biochim. biophys. acta, Mol. basis dis
/
Biochimica et biophysica acta. Molecular basis of disease
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Países Bajos