| Summary: | <p>Abstract</p> <p>Background</p> <p>The megencephaly mouse, <it>mceph/mceph</it>, is epileptic and displays a dramatically increased brain volume and neuronal count. The responsible mutation was recently revealed to be an eleven base pair deletion, leading to a frame shift, in the gene encoding the potassium channel Kv1.1. The predicted MCEPH protein is truncated at amino acid 230 out of 495. Truncated proteins are usually not expressed since nonsense mRNAs are most often degraded. However, high <it>Kv1.1 </it>mRNA levels in <it>mceph/mceph </it>brain indicated that it escaped this control mechanism. Therefore, we hypothesized that the truncated Kv1.1 would be expressed and dysregulate other Kv1 subunits in the <it>mceph/mceph </it>mice.</p> <p>Results</p> <p>We found that the MCEPH protein is expressed in the brain of <it>mceph/mceph </it>mice. MCEPH was found to lack mature (Golgi) glycosylation, but to be core glycosylated and trapped in the endoplasmic reticulum (ER). Interactions between MCEPH and other Kv1 subunits were studied in cell culture, <it>Xenopus </it>oocytes and the brain. MCEPH can form tetramers with Kv1.1 in cell culture and has a dominant negative effect on Kv1.2 and Kv1.3 currents in oocytes. However, it does not retain Kv1.2 in the ER of neurons.</p> <p>Conclusion</p> <p>The <it>megencephaly </it>mice express a truncated Kv1.1 in the brain, and constitute a unique tool to study Kv1.1 trafficking relevant for understanding epilepsy, ataxia and pathologic brain overgrowth.</p>
|
|---|
