GATOR opathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations
Open accessAbstract
The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.
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Studies employing deep targeted sequencing in resected brain tissue highlight the role of brain-restricted somatic mosaic variants in nearly all of these genes in FCD type II, sometimes with hemimegalencephaly, with variant allele frequencies as low as 0.01%.
“Studies employing deep targeted sequencing in resected brain tissue highlight the role of brainrestricted somatic mosaic variants in nearly all of these genes in FCD type II, sometimes with hemimegalencephaly 123 , with variant allele frequencies as low as 0.01% 130 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [123]
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- Authors
- Iffland, P. H., Carson, V., Bordey, A., & Crino, P. B.
- Affiliations
- University of Maryland, Baltimore (US)
- Clinic for Special Children (US)
- Department of Neurosurgery Yale University School of Medicine New Haven Connecticut
- Corresponding author
- Crino, Peter B.
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2019-10-17
- Volume
- 60
- Issue
- 11
- Pages
- 2163-2173
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- PMC
- PMC7155771
- OpenAlex
- W2981122284
- Cited by
- 84
- References
- 67
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 16 · 2023: 18 · 2022: 7 · 2021: 14 · 2020: 5 · 2018: 1
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH‐16‐1‐0164)
- National Institute of Neurological Disorders and Stroke (R01NS094596, R01NS099452)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- GATOR1 complex, DEPDC5, NPRL3, NPRL2, mTOR signaling, malformations of cortical development, focal cortical dysplasia, hemimegalencephaly, megalencephaly, drug-resistant epilepsy, amino acid regulation, cortical lamination, neuronal excitability, mTOR inhibition, intellectual disability
- MeSH terms
- Animals, Epilepsy, Humans, Mutation, GTPase-Activating Proteins, Tumor Suppressor Proteins, Malformations of Cortical Development, TOR Serine-Threonine Kinases
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