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Commentary: GATOR Complex‐Associated Epilepsies

In 1995, a missense variant in CHRNA4 was identified as the cause of nocturnal frontal lobe epilepsy in a large Australian family. Since then, many focal epilepsy genes have been discovered, with a focus mostly on ion channels. However, even though focal epilepsies (such as temporal lobe epilepsy and frontal lobe epilepsy) are the most common forms of epilepsy, the fraction of families for which a causative pathogenic variant could be identified has remained rather low. Nearly 20 years later two groups revealed truncating variants in the gene encoding the disheveled, Egl-10, and pleckstrin (DEP) domain–containing 5 protein DEPDC5 to be associated with familial focal epilepsy with variable foci (FFEVF). Together with the natriuretic peptide receptor 2-like proteins NPRL2 and NPRL3, DEPDC5 forms the gap activity towards rags 1 (GATOR1) complex, a repressor of the mechanistic target of rapamycin complex 1 (mTORC1). The link of familial focal epilepsies to the GATOR1 protein complex was followed by the identification of loss-of-function variants NPRL2 and NPRL3 in additional families with FFEVF and has broadened our understanding of focal epilepsy beyond channelopathies. The current study of Weckhuysen et al. investigated to what extent GATOR complex genes are involved in familial focal epilepsy. Using a sequencing panel targeting several GATOR1 and GATOR2 complex genes, the authors screened a cohort of 93 individuals with focal epilepsy, many of whom had focal cortical dysplasia (FCD). Among these individuals, three truncating variants were detected in NPRL2 (n = 1) and NPRL3 (n = 2), corresponding to 3.2% of the complete cohort. Moreover, among 50 individuals not previously screened for DEPDC5, Weckhuysen et al. identified four truncating variants (8%) in DEPDC5. These findings do not only illustrate a diagnostic yield of >10%, but prove the concept of lack of GATOR1 inhibition in the mTORC1 as a cause of focal epileptogenesis in autosomal dominant pedigrees. In addition to previous reports on FCD in DEPDC5-associated focal epilepsy, Weckhuysen et al. not only provided further supporting evidence for DEPDC5-associated FCD, but also showed that all three detected variants in NPRL2 and NPRL3 were associated with FCD in some of the affected family members. Thus lack of GATOR1 inhibition in general can be considered as a predisposing factor to the development of FCD, explaining focal epileptogenesis in these individuals. This conclusion has been further supported by the observation of somatic variants in MTOR, another main component of mTORC1, in dissected FCD tissue from patients with focal epilepsy. It remains unclear to what extent pathogenic variants in GATOR2 play a role in the development of FCD and focal epilepsy. Because GATOR2 inhibits GATOR1, one would expect that gain-of-function variants in GATOR2 complex genes may mediate a similar effect on downstream mTORC1 as loss-of-function variants in GATOR1. However, in comparison to truncations that can easily be acknowledged as loss-of-function variants, missense variants of unknown significance are far more difficult to recognize as a potential cause of gain-of-function. In addition to clearly pathogenic variants in GATOR1, Weckhuysen et al. also detected several missense variants of unknown significance in GATOR1 and GATOR2 complex genes. To what extent these variants are pathogenic, and how they increase the impact of GATOR complex disorders in focal epilepsies, remains to be elucidated. The involvement of the GATOR complex genes in this spectrum of disorders opens a new field not only with respect to pathogenesis, but also with regard to potential treatment approaches, as the lack of GATOR1 inhibition with its consecutive overactivation of mTORC1 is a promising therapeutic target. Because of these considerations, the study by Weckhuysen et al. helps pave the way toward a better understanding of the role of GATOR complex genes in focal epilepsies.