Functional studies of mutatons in SCN2A gene associated with early-onset epilepsy

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Dokumentart: Dissertation
Date: 2019-01-22
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Holger, Lerche (Prof. Dr.)
Day of Oral Examination: 2019-01-07
DDC Classifikation: 610 - Medicine and health
Keywords: Epilepsie
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Human brain VGSCs are related to the action potential of the neuron. Functional changes happen in human VGSCs can induce neuronal hyperexcitability and result in seizures. SCN2A which codes for the hNav1.2 channel, is one important gene associated with neonatal-onset epilepsy. Neonatal-onset epilepsy is defined as an onset within four weeks after birth. A severe neonatal-onset epilepsy can cause permanent developmental regression and resistance to AEDs treatment. In this dissertation, both A1659V and I1640M mutations of SCN2A associated with neonatal-onset epilepsy were functionally analyzed using electrophysiology technique. Either the WT or the mutation, with the hβ1 and hβ2, were co-expressed in tsA201 cells for functional studies. Both mutations shifted in depolarization direction in fast inactivation and speed up recovery from it. Moreover, A1659V mutation presented increasing persistent INa and slower fast inactivation. All these functional changes indicated clear GOF effects. These functional consequences predict an increase in channel availability for action potentials, a shorter refractory period and more inward sodium current that can depolarize the neuronal cell membrane. The detected changes can therefore well explain a neuronal hyperexcitability which can result in epileptic seizures. Further studies need to be performed using neurons and neuronal networks to understand neuronal hyperexcitability. First consequences for treatment result from such studies since GOF mutations in SCN2A can be well treated by Na+ channel blockers. However, further drugs are needed, since not all patients respond and some have severe side effects.

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