A possible link between KCNQ2- and STXBP1-related encephalopathies: STXBP1 reduces the inhibitory impact of syntaxin-1A on M current

Study finds a possible relationship between KCNQ2 and the STXBP1 gene that has been identified as a cause of Ohtahara Syndrome

Background: The potassium channels control the electrical currents sent by the neurons. Mutations of the KCNQ2 gene coding for a component of these potassium channels cause early-onset epileptic encephalopathies. Mutations in the STXBP1 gene, which codes for syntaxin binding protein 1, and causes Ohtahara Syndrome, can cause similar symptoms to those seen in patients with KCNQ2 mutations. The similarities in symptoms caused by these two different gene mutations suggest there is a possible link between STXBP1 and potassium channels.

Potassium channels are known to be modulated by syntaxin-1A, a protein encoded by the STX1A gene, which inhibits the electrical activity of the potassium channels (or M-current). This study evaluated whether the STXBP1 gene, which is a cause of Ohtahara Syndrome and is related to STX1A, prevents syntaxin-1A from limiting the activity of the potassium channel.

Methods: The study examined the electrical signals in cells grown with various mutation combinations to evaluate the interaction between the various proteins expressed by the STXBP1 and STX1A genes.

Results:
The study demonstrated that syntaxin-1A decreased the electrical currents (M currents) of the potassium channel by binding to the channel. The study showed that syntaxin binding protein 1 (encoded by STXBP1) did not directly affect the electrical current of the potassium channel, but it interfered with the binding of syntaxin-1A. In effect, syntaxin binding protein 1 stopped the syntaxin-1A from interfering with the potassium channel activity. When there is a mutation in the STXBP1 gene affecting the production of syntaxin binding protein 1 (as in Ohtahara Syndrome), the syntaxin-1A is able to interfere with potassium channel activity.

Significance:
The results show that there is a link between STXBP1 (a gene found to cause Ohtahara Syndrome) and potassium channels, indirectly, by way of the syntaxin-1A protein. It suggests that defects in the activity of the potassium channel similar to those seen with KCNQ2 mutations could also be caused by certain mutations in STXBP1. The protein syntaxin-1A may be important for regulating potassium channel activity and signaling by the neurons.

Devaux, J., Dhifallah, S., De Maria, M., Stuart-Lopez, G., Becq, H., Milh, M., Molinari, F. and Aniksztejn, L. (2017), A possible link between KCNQ2- and STXBP1-related encephalopathies: STXBP1 reduces the inhibitory impact of syntaxin-1A on M current. Epilepsia, 58: 2073–2084. doi:10.1111/epi.13927