AKT3, a key component of the PI3K-AKT-MTOR pathway, is highly expressed in the brain, and its activating variants cause megalencephaly and cortical malformations. In this study, we functionally verified a novel missense AKT3 variant (p.Q78R) identified in a patient with extreme megalencephaly and intractable epilepsy. We transiently transfected HEK-293T cells with the AKT or AKT3 and observed a significant increase of phospho-S6, a marker of mTOR complex 1 (mTORC1) activity, in AKT3 transfected cells. Furthermore, considering its application in epilepsy treatment research, we identified a small interfering RNA (siRNA) capable of reducing the mRNA levels of AKT without affecting the expression levels of AKT3. Finally, the siRNA we identified specifically suppressed the AKT3-mediated mTORC1 activity, suggesting that this allele-specific siRNA approach holds promise for ameliorating the pathological condition.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s10038-025-01329-x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Functional verification and allele-specific silencing of a novel AKT3 variant that causes megalencephaly, polymicrogyria and intractable epilepsy.
J Hum Genet
March 2025
Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
AKT3, a key component of the PI3K-AKT-MTOR pathway, is highly expressed in the brain, and its activating variants cause megalencephaly and cortical malformations. In this study, we functionally verified a novel missense AKT3 variant (p.Q78R) identified in a patient with extreme megalencephaly and intractable epilepsy.
View Article and Find Full Text PDFThe phenotypic and genetic spectrum of AKT3-related neurodevelopmental condition.
Sci Rep
March 2025
Department of Pediatrics, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
This study was undertaken to expand the phenotypic and genetic spectrum of AKT3-related neurodevelopmental disorders and to investigate genotype-phenotype correlations. To date, more than 200 patients with AKT3-related disorders have been identified, including those with AKT3 single nucleotide variants and copy number variations affecting the AKT3 gene. Adding our three newly diagnosed patients, the total number of patients with AKT3 single nucleotide variant-related neurodevelopmental disorders is now 61.
View Article and Find Full Text PDFThe genetic landscape and classification of infantile epileptic spasms syndrome requiring surgery due to suspected focal brain malformations.
Brain Commun
January 2025
Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia.
Infantile epileptic spasms syndrome is a severe epilepsy of infancy that is often associated with focal malformations of cortical development. This study aimed to elucidate the genetic landscape and histopathologic aetiologies of infantile epileptic spasms syndrome due to focal malformations of cortical development requiring surgery. Fifty-nine children with a history of infantile epileptic spasms syndrome and focal malformations of cortical development on MRI were studied.
View Article and Find Full Text PDFAnalysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR.
Nat Commun
November 2024
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing.
View Article and Find Full Text PDFMulti-disciplinary team approach for pediatric hemimegalencephaly: Insights from a single institutional case series.
Epilepsia Open
December 2024
Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
Recent genetic studies have revealed that hemimegalencephaly (HME) is a multi-system disorder associated with germline or mosaic variants within the PI3K-mTOR-GATOR1 signaling pathways. Patients with HME typically develop drug-resistant epilepsy necessitating extensive evaluation, hemispherectomy, and long-term management. We describe the role of a multidisciplinary team (MDT) for the diagnosis and management of recent patients with HME at UCLA who underwent hemispherectomy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!