mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly
Camila A B Garcia1, Simone C S Carvalho2, Xiaoxu Yang3
1Department of Surgery and Anatomy Ribeirão Preto Medical School University of São Paulo (USP) Ribeirao Preto SP Brazil.
Objectives:
Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME.
Methods:
Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5.
Results:
These results strengthen the hypothesis that somatic variants in PI3K-Akt-mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation.
Significance:
In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.
Insights
Researchers identified genetic variants in mTOR pathway genes in patients with hemimegalencephaly (HME). These findings link mTOR pathway gene mutations to HME development and brain malformations, aiding future genetic diagnoses.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Defects in the mammalian target of rapamycin (mTOR) pathway are increasingly linked to hemimegalencephaly (HME).
- The mTOR pathway is crucial for regulating cellular functions including growth, metabolism, and survival.
- Understanding genetic underpinnings of HME is vital for diagnosis and treatment.
Purpose of the Study:
- To identify specific genetic variants within the mTOR signaling pathway in patients diagnosed with HME.
- To investigate the role of these variants in the pathogenesis of HME.
- To correlate genetic findings with clinical presentation and brain malformations.
Main Methods:
- Utilized amplicon and whole exome sequencing (WES) on resected brain and blood samples from five HME patients.
- Focused on identifying mosaic variants in key mTOR pathway genes.
- Analyzed variants in genes including MTOR, PIK3CA, and DEPDC5.
Main Results:
- Identified pathogenic mosaic variants in MTOR, PIK3CA, and DEPDC5 genes in HME patients.
- Confirmed the contribution of somatic variants in the PI3K-Akt-mTOR pathway to HME.
- Demonstrated DEPDC5 variants' role in cortical malformations via mTORC1 hyperactivation.
- Provided insights into the timing of variant occurrence during brain development and its impact on malformation severity.
Conclusions:
- Findings strengthen the association between somatic variants in PI3K-Akt-mTOR pathway genes and HME.
- The study highlights DEPDC5's significance in mTORC1-mediated cortical development.
- Future research will likely uncover more variants, enabling genotype-phenotype correlations for genetic diagnosis and outcome prediction.
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...