A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids

Ying Xu; Rongrong Lu; Hao Li; Weijun Feng; Rui Zhao

doi:10.1016/j.bbadis.2024.167232

A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids

Biochim Biophys Acta Mol Basis Dis. 2024 May 15;1870(6):167232. doi: 10.1016/j.bbadis.2024.167232. Online ahead of print.

Authors

Ying Xu¹, Rongrong Lu², Hao Li³, Weijun Feng⁴, Rui Zhao⁵

Affiliations

¹ Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Department of Neurosurgery, Children's Hospital of Fudan University, Fudan University, Shanghai 201102, China.
³ Department of Neurosurgery, Children's Hospital of Fudan University, Fudan University, Shanghai 201102, China; Department of Neurosurgery, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen 361006, China.
⁴ Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen 361006, China. Electronic address: fengweijun@fudan.edu.cn.
⁵ Department of Neurosurgery, Shanghai Children's Hospital, Shanghai 200333, China. Electronic address: dr_zhaorui@fudan.edu.cn.

PMID: 38759814
DOI: 10.1016/j.bbadis.2024.167232

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.

Keywords: AKT3 mutations; Cortical organoids; Focal malformations of cortical development (FMCDs); Mosaic and somatic mutations, dysmorphic neurons.