Mechanism of MTOR-related malformations of cortical development
Paediatric epileptogenic malformations of cortical development (MCDs) leads to focal cortical dysplasia, hemimegalencephaly and are mostly treated surgically by the resection of epileptic cortex.
Brain somatic or germline mutations in the AKT/PI3K/DEPDC5/MTOR genes have been identified as cause for MCDs.
The researchers study the mechanisms underlying epilepsy in focal cortical dysplasia.
They show that somatic brain mutations in mTOR drive the deregulation of chloride co-transporters, leading to paradoxical GABA depolarization and neuronal hyperexcitability.
Mechanistically, the authors show that a protein interaction network through a phosphorylation cascade between MTOR and WNK1/SPAK-OSR1 leading to deregulation of chloride cotransporters, increased neuronal Cl− levels and GABAA dysfunction in malformations of cortical development, linking genomic defects and functional effects.
