| Autor: |
Yunxiang Liao, Deprez, Liesbet, Maljevic, Snezana, Pitsch, Julika, Claes, Lieve, Hristova, Dimitrina, Jordanova, Albena, Ala-Mello, Sirpa, Bellan-Koch, Astrid, Blazevic, Dragica, Schubert, Simone, Thomas, Evan A., Petrou, Steven, Becker, Albert J., De Jonghe, Peter, Lerche, Holger |
| Předmět: |
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| Zdroj: |
Brain: A Journal of Neurology; May2010, Vol. 133 Issue 5, p1403-1414, 12p, 1 Color Photograph, 1 Diagram, 1 Chart, 3 Graphs |
| Abstrakt: |
Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na+ channel NaV1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na+ channel NaV1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na+ current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of NaV1.2 and of another voltage-gated Na+ channel, NaV1.6, using immunohistochemistry and real-time reverse transcription--polymerase chain reaction in mouse brain slices. We found that NaV1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by NaV1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant NaV1.2 channels. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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