Functional insights from genetic channelopathies

Published on July 1, 2014   50 min

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Other Talks in the Series: The Genetic Basis of Neurological Disorders

0:00
Hello. I'm Stephanie Schorge, and I am at the Royal Society University Research Fellow working here in the Department of clinical and experimental epilepsy at the UCL Institute of Neurology. And I'm going to talk today about some functional insights we have from human genetic channelopathies and how we think they are linked to disease.
0:21
So the aim of this lecture, to begin with, is to first of all, give you an overview of what channelopathies are without giving an entire list. And then I'm going to give an overview of how genes are made into ion channels in five easy steps. And for each of those steps I'm going to illustrate with a specific example of a particular channelopathy that I've carefully cherry picked to focus in on one step. And there are many, many other channelopathies that I won't mention, but the ones that I do mention are going to be those that I have tried to isolate specifically to highlight those steps.
0:52
So we're in the genomic era. And that makes life much, much easier for people who link ion channels to diseases. And this means that at this point, finding a mutation in an ion channel is less about finding the gene and more just about sequencing ion channels. And the reason that most ion channel-related diseases have a neurological component is not because neurons have all the ion channels, but just that neurons have most of the ion channels. All cells, all living cells have ion channels, and you can almost define a living cell by the presence of ion channels. And neurons in particular not just because they have ion channels, but because just about every ion channel you have is in some neuron somewhere. So if you have a mutation in an ion channel genes, there's a very high probability it's going to affect some neuron somewhere. So in the original incarnation, because people who study ion channels frequently have been biophysicists who look at the functioning of intact channels, our first conception was to find these mutations in ion channel genes and to express those and to look at the channelopathy as a change in the function of an intact channel with one amino acid changed, or one or two inserted or deleted. However, since we've entered this era of vast amounts of sequencing, we realize that many channelopathies, if not most channelopathies, they don't just disrupt a single nucleotide and a single amino acid, but they will change the product of the gene before the mRNA, the protein, ever gets made and into the membrane where the channel would normally work. And as I'll try to link to throughout this lecture, the treatments that we have for diseases associated with channelopathies are just beginning to recognize that we may not be treating a channel in the membrane. We may be treating an RNA before it becomes a channel.
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Functional insights from genetic channelopathies

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