Funding tool: Dissertations
Project-ID: FTI22-D-013
Project start: 01. April 2023
Project end: 31. März 2026
Runtime: 36 months / finished
Funding amount: ca. € 71.000,00

Brief summary:
Neonatal seizures are abnormal electrical activity in the brain that happen in the first months of life and, if idiopathic, they are often a sign of a serious underlying neurodevelopmental disorder. There are 8 previously reported cases with infantile-onset epilepsy due to bi-allelic loss of function mutations in the CACNA2D2 gene encoding for the a2d-2 protein, an auxiliary subunit of voltage-gated calcium channels. In my proposed PhD project, I will study the disease mechanism of a novel homozygous point mutation in a2d-2 found in a newborn with neonatal seizures. The entry of calcium into cells is tightly regulated by voltage-gated calcium channels, which in the central nervous system consist of a pore forming a-1 subunit and the auxiliary b and a2d subunits. The classical roles of auxiliary a2d subunits on voltage-gated calcium channels are widely recognized. However, important role in synapse formation and differentiation has emerged from recent studies that may be independent from their channel dependent function. This synaptic function highlights their importance in brain connectivity and therefore it is not surprising that a lot of mutations in CACNA2D genes have been linked to a variety of neurological and neuropsychiatric disorders such as epilepsy, autism, and schizophrenia. However, until today little is known about the underlying pathophysiological mechanisms and whether a synaptic mechanism is involved. In contrast to previous studies, I will study the pathophysiological mechanism by addressing the synaptic functions beside the channel dependent functions of a2d proteins. Studying this particular case will first provide new insights into the CACNA2D2 gene as risk gene for neonatal seizures, second contribute to our understanding of the role of a2d subunits in general synaptic functions, lastly and most importantly, contribute to the development of novel therapeutic approaches for this case and potential future similar disease phenotypes.

Keywords:
voltage-gated calcium channels, CACNA2D2 gene, synapse formation, epilepsy, neonatal seizures, site directed mutagenesis

Results