Functional studies of sodium channel mutations contributing to severe childhood epilepsy
- Research Opportunity
- PhD, Honours
- Number of Honour Places Available
- Medicine and Radiology
- Florey Institute of Neuroscience & Mental Health
Developmental and early epileptic encephalopathies (DEE) are a group of devastating disorders with poor prognosis and complex etiology presenting in childhood. De novo mutations in the SCN2A gene encoding for the voltage-gated sodium (Nav) channel, type II α subunit (Nav1.2), represent a major cause of DEE. There is an urgent need for a comprehensive understanding of the biophysical, neurophysiological, and clinical impacts of different mutation classes for diagnosis and for the development of disease mechanism-based therapies.
Here, we will use conventional voltage clamp and dynamic clamp approaches to investigate selected human SCN2A variants affecting Nav1.2 channel function. In voltage clamp, the biophysical properties of voltage-gated Nav1.2 channel variants will be studied. In dynamic clamp, the neurophysiological consequences of individual variants will be determined. Dynamic clamp produces a real-time coupling between the mammalian cell expressing Nav1.2 channel and a biophysically realistic in silico cell to generate a hybrid neuron model that predicts the impact of ion channel variation on neuronal excitability (see Berecki et al. Proc Natl Acad Sci U S A. 2018.115:E5516-E5525). This method represents a significant advance over conventional electrophysiological and computational modelling approaches that are the only option currently available. Dynamic clamp is well positioned to impact diagnosis in genetic epilepsy and is particularly relevant in the current era of precision medicine.
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Research NodeFlorey Institute of Neuroscience & Mental Health
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