Disheveled EGL-10 and pleckstrin domain-containing protein 5 (DEPDC5) is a key member of the GAP activity toward rags complex 1 complex, which inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway. DEPDC5 loss-offunction mutations lead to an aberrant activation of the mTOR signaling. At neuronal level, the increased mTOR cascade causes the generation of epileptogenic dysplastic neuronal circuits and it is often associated with malformation of cortical development. The DEPDC5 phenotypic spectrum ranges from sporadic early-onset epilepsies with poor neurodevelopmental outcomes to familial focal epilepsies and sudden unexpected death in epilepsy; a high rate of inter- and intrafamilial variability has been reported. To date, clear genotype-phenotype correlations have not been proven. More studies are required to elucidate the significance of likely pathogenic/variants of uncertain significance. The pursuit of a molecular targeted antiepileptic therapy is a future challenge.

The spectrum of DEPDC5-related epilepsy

Salomone G.;Comella M.;Portale A.;Pecora G.;Costanza G.;Sciuto S.;Pratico E. R.
;
Falsaperla R.
2021-01-01

Abstract

Disheveled EGL-10 and pleckstrin domain-containing protein 5 (DEPDC5) is a key member of the GAP activity toward rags complex 1 complex, which inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway. DEPDC5 loss-offunction mutations lead to an aberrant activation of the mTOR signaling. At neuronal level, the increased mTOR cascade causes the generation of epileptogenic dysplastic neuronal circuits and it is often associated with malformation of cortical development. The DEPDC5 phenotypic spectrum ranges from sporadic early-onset epilepsies with poor neurodevelopmental outcomes to familial focal epilepsies and sudden unexpected death in epilepsy; a high rate of inter- and intrafamilial variability has been reported. To date, clear genotype-phenotype correlations have not been proven. More studies are required to elucidate the significance of likely pathogenic/variants of uncertain significance. The pursuit of a molecular targeted antiepileptic therapy is a future challenge.
2021
Agonists of GATOR1
DEPDC5
Epilepsy surgery
Focal cortical dysplasia
Focal epilepsy
GATOR1
MTORC1 inhibitors
MTORC1 pathway
MTORopathies
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/508421
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