Among the Nedd4 family E3s, Nedd4-2 (N4-2) is of particular interest because missense mutations of evolutionarily conserved residues (S233L, E271A, and H515P) were found in patients with familial photosensitive epilepsy (Dibbens et al., 2007; Vanli-Yavuz et al., 2015) and several other de novo mutations in N4-2 were reported in epilepsy patients (Allen et al., 2013), indicating that N4-2 is a critical regulator of neuronal network activity. This evidence concerns the gene NEDD4L and epilepsy.