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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 <jats:italic>DEPDC5<\/jats:italic>, <jats:italic>NPRL3<\/jats:italic>, or <jats:italic>NPRL2<\/jats:italic> are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring <jats:italic>DEPDC5<\/jats:italic>, <jats:italic>NPRL3<\/jats:italic>, or <jats:italic>NPRL2<\/jats:italic> gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either <jats:italic>DEPDC5<\/jats:italic> or <jats:italic>NPRL3<\/jats:italic> share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with <jats:italic>DEPDC5<\/jats:italic>, <jats:italic>NPRL3<\/jats:italic>, or <jats:italic>NPRL2<\/jats:italic> variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non\u2010lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either <jats:italic>Depdc5<\/jats:italic> or <jats:italic>Nprl3<\/jats:italic> 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 <jats:italic>DEPDC5<\/jats:italic>, <jats:italic>NPRL3<\/jats:italic>, or <jats:italic>NPRL2<\/jats:italic>.<\/jats:p>","DOI":"10.1111\/epi.16370","type":"journal-article","created":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T04:23:54Z","timestamp":1571372634000},"page":"2163-2173","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["<scp>GATOR<\/scp>opathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations"],"prefix":"10.1111","volume":"60","author":[{"suffix":"II","given":"Philip H.","family":"Iffland","sequence":"first","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine Baltimore 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