Medicine (Austin & Northern Health) - Research Publications

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Mutations in Mammalian Target of Rapamycin Regulator DEPDC5 Cause Focal Epilepsy with Brain Malformations

Scheffer, IE ; Heron, SE ; Regan, BM ; Mandelstam, S ; Crompton, DE ; Hodgson, BL ; Licchetta, L ; Provini, F ; Bisulli, F ; Vadlamudi, L ; Gecz, J ; Connelly, A ; Tinuper, P ; Ricos, MG ; Berkovic, SF ; Dibbens, LM (WILEY-BLACKWELL, 2014-05)

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.