De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly
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De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8-40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.
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Somatic mutations identified in human hemimegalencephaly (HMG) reveal the dysregulated PI3K-AKT3-mTOR pathway as the causative mechanism.
“Somatic mutations that were identified in human hemimegalencephaly (HMG) revealed the dysregulated phosphoinositide 3-kinase (PI3K)–AKT3-mTOR pathway as the causative mechanism (Lee et al., 2012; Poduri et al., 2012; Riviere et al., 2012).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Lee et al., 2012
Additional somatic mutations causing HMG implicate key upstream and downstream components of the PI3K-AKT3-mTOR pathway, namely PI3K and mTOR.
“Additional somatic mutations causing HMG have been identified that implicate key upstream and downstream components of this pathway, namely PI3K and mTOR (Lee et al., 2012; Riviere et al., 2012).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Lee et al., 2012
The AKT3 Glu17Lys mutation renders AKT3 constitutively active.
“AKT3 is a RAC-gamma serine/threonine protein kinase that is highly expressed in the developing neocortex, and the Glu17Lys mutation renders AKT3 constitutively active (Lee et al., 2012; Poduri et al., 2012).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Lee et al., 2012
Levels of mosaicism as low as 8% are sufficient to disrupt the normal architecture and function of the neocortex in HMG.
“Surprisingly, levels of mosaicism as low as 8% are sufficient to disrupt the normal architecture and function of the neocortex in HMG (Evrony et al., 2012; Lee et al., 2012; Poduri et al., 2012; Riviere et al., 2012).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Lee et al., 2012
A recurrent AKT3 mutation (Glu17Lys) was identified in HMG by direct study of resected tissue.
“Direct study of resected tissue led to the identification of a recurrent AKT3 mutation (Glu17Lys) in HMG.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Lee et al., 2012
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Self-citation
- Authors
- Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., & Gleeson, J. G.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Cedars-Sinai Medical Center (US)
- Broad Institute (US)
- Corresponding author
- Mathern, Gary W
- Gleeson, Joseph G
- ORCID
- Venue
- Nature Genetics
- Published
- 2012-06-24
- Volume
- 44
- Issue
- 8
- Pages
- 941-945
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4417942
- OpenAlex
- W2079701909
- Cited by
- 703
- References
- 42
- Citations by year
- 2026: 19 · 2025: 32 · 2024: 28 · 2023: 32 · 2022: 38 · 2021: 50 · 2020: 84 · 2019: 57 · 2018: 48 · 2017: 59 · 2016: 54 · 2015: 72 · 2014: 65 · 2013: 53 · 2012: 10
- FWCI
- 56.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- University of California, San Diego
- National Human Genome Research Institute (U54HG003067)
- National Institute of Neurological Disorders and Stroke (R01NS041537, R01NS048453, R01NS052455, R01NS038992, P30NS047101, R01NS083823)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD070494)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- hemimegalencephaly, PIK3CA, AKT3, mTOR, PI3K/AKT/mTOR pathway, mTOR signaling, drug-resistant epilepsy, hemispherectomy, genetic mosaicism, gain-of-function
- MeSH terms
- Child, Preschool, DNA Mutational Analysis, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Mosaicism, Signal Transduction, Phosphatidylinositol 3-Kinases, Mutation, Missense, Proto-Oncogene Proteins c-akt, Malformations of Cortical Development, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Exome
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