Kids with brain development issues caused by KCNQ2 variants face a tough time getting diagnosed. This is because these variants are quite diverse and their effects aren't clear. Let's take a look at one child who had seizures right after birth, along with moderate brain development problems. This child had a specific variant called KCNQ2 G256W.

Scientists studied this variant using advanced microscopy models. They found that G256 plays a crucial role in connecting different parts of the KCNQ2 channel, like the S5 segment, the pore turret, and the path where ions flow. When this variant was mixed with normal KCNQ2 subunits in lab cells, it reduced their ability to conduct signals. However, a drug called Ezogabine could partly fix this problem.

Mice with this G256W variant had seizures and died early. Brain slices from these mice showed overactive cells in a region called the hippocampus. The variant also changed where the KCNQ2 and KCNQ3 proteins were located in the cells, moving them from the axon initial segments to the cell bodies. Despite normal mRNA levels, the protein levels in these mice were about 50% lower.

These findings suggest that the G256W variant causes issues in several ways, including reducing the ability to conduct signals, changing where proteins go in cells, and making the proteins less stable. This research introduces a new role for the KCNQ2 pore turret and provides a valid animal model for KCNQ2 encephalopathy. These results, from the structure of the protein to behavior, could be useful for many kids with KCNQ2 encephalopathy, as most have variants near the selectivity filter.

Unraveling the Mysteries of KCNQ2 Encephalopathy in Kids

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