# SEA and GATOR 10 Years Later
## 8 GATOR in Human Diseases
### Epilepsies and Brain Malformations--DEPDC5 and Others  
In 2013, DEPDC5 was reported as the first gene implicated in familial focal epilepsies by [PERSON] and [PERSON] groups [175; 176]. In the following years, it became clear that mutations in DEPDC5 are also related with brain malformations, notably with focal cortical dysplasia (FCD), which is a major cause of drug-resistant epilepsy [177] and can be associated with sudden unexpected death in epilepsy (SUDEP) [178]. In 2016, mutations related with focal epilepsies, familial cortical dysplasia and SUDEP were also reported for Nprl2 and Nprl3 [174; 179; 180]. Since then, more than 140 variants of GATOR1 genes have been found in up to 37% of patients with familial focal and in other forms of epilepsies [181]. These variants include loss-of-function mutations (67%), missense mutations (27%), splice site changes (4%), frameshifts and copy number variants (~1%). Interestingly, the distribution of mutations in an epilepsy cohort differs drastically from the overall distribution of GATOR1 mutations listed in the gnomAD database, where loss-of-function represents only 4% of variants, with the majority (88%) being missense mutations. Importantly, histopathological analysis of brain tissues resected from individuals with GATOR1 gene mutations demonstrate the hyperactivation of mTOR1 pathway, suggesting that mTOR1 signaling plays an important role in brain development [174; 179; 180]. Nearly 85% of GATOR1 mutations in epilepsies account for changes in DEPDC5 with both somatic and germline mutations detected all through the gene without clustering. Initially, it was not clear how germline _Depdc5_ mutations can cause FCD, especially taking into account that these mutations are often dominantly inherited from an asymptomatic carrier parent [181] and that in rodent models _Depdc5+-_ constitutive heterozygous mutations do not exhibit an epileptic phenotype [21; 170]. The discovery of second hit somatic mutations in trans, which led to a biallelic inactivation in a subset of brain cells, explained this phenomenon [182; 183]. Nprl2 and Nprl3 mutation are less frequent (6% and 9%, respectively), which might be partially related with the fact that their involvement in epilepsies and brain malformations has been tested in a low number of people [26; 181]. Cases with simultaneous mutations in different GATOR1 genes have not been described thus far. Several _Nprl2_ or _Nprl3_ variants found in individuals with FCD or hemimega-loencephal (HME) have been reported recently [184; 185]. Interestingly, _NPRL3_ single nucleotide polymorphism has been associated with ischemic stroke susceptibility and post-stroke mortality [186], which can be related with increased mTOR activity, that is known to accelerate brain recovery after stroke. The role of NPRL3 in this disease is most probably related with its function in focal epilepsies that might occur in ischemic cerebrovascular disorders [187]. Finally, genetic alternations of KICSTOR complex, required for GATOR1-mediated repression of mTOR1 signaling (see above), have also been linked to epilepsies and brain malformations [188; 189; 190]. Thus, it is evident that GATOR1 plays an essential role in cortical formation and development. Mutations of GATOR1 components became important features of \"mTORopathies\" --a set of pathological conditions characterized by brain malformations, neurological disorders and mTOR1 hyperactivity due to either gain-of-function mutations in a pathway activators (e.g., _AKT_, _RHEB_, _MTOR_ itself) or loss-of-function mutations of inhibitors (e.g., _TSC1_, _TSC2_) [191; 192]. However, mutations of GATOR1 genes seem to result in a broader spectrum of neurological disorders than other \"mTORopathic\" genes. Not only are these mutations highly related with medically intractable epilepsies and, especially SUDEP, but they are also observed in autism spectrum disorders [150] and could be implicated in Parkinson's disease [193].