Structural and functional studies of HCN1 channel mutations causing early infantile epileptic encephalopathy

This research project is focused on the study of the molecular mechanisms underlying a recently described form of early infantile epileptic encephalopathy (EIEE). EIEE is a severe progressive disease of the newborn and children, characterized by drug-resistant epileptic seizures and mental retardation or premature death. It is caused by the sporadic mutation of a gene usually encoding a kind of protein called "ion channel". Ion channels span cell membranes and regulate the flux of electric charges across them. HCN1 gene, belonging to a well-studied family of channels controlling cardiac and neuronal pacemaker activity, has been recently added to the list of EIEE-causing genes. Our research group produced relevant publications about HCN in the past. We now set out to produce soluble fragments of the normal or mutant HCN1 protein in order to study its biochemistry and describe its structure at atomic resolution. Moreover, we intend to produce the full protein in frog oocytes to study its electrical properties and the impairment due to the disease. The aim of this study is to fully understand the mechanisms underlying this form of epilepsy; this in turn will allow to design taylored drugs for the treatment of the disease.