Uncovering the mysteries of human CACNA1C using new technologies

Elizabeth Tunbridge, Associate Professor, Oxford University

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In my 20 years of studying the rich wonders of the human brain, I have come to view research as a process of revealing how little we know! This has certainly been true in the case of my lab’s recent research into CACNA1C.

In it, we asked a simple theoretical question: how many different types of calcium channel does the CACNA1C code for in human brain? The answer turned out to be far more complex – and exciting – than we had anticipated.

We investigate how individual genes influence human brain function. We first need to understand what these genes code for. This question is not as straightforward as it might first appear, because most genes don’t encode a single molecule, but instead ‘families’ of related molecules.

As you might expect, the precise set of molecules that a gene encodes depends on the cell in question; for example, heart cells need to make a different set of molecules to brain cells as they have very different functions.

To do this, different cell types ‘read’ the genome (the DNA ‘instruction manual’ that is the same in all cells) in different ways; shuffling its basic instructions to give rise to the precise molecular ‘recipe’ that the individual cell needs. In this way, the single CACNA1C gene can potentially encode many similar, but subtly distinct, calcium channels.

Although we know that this ‘shuffling’ is crucial, we know surprisingly little about what human genes encode. There are two reasons for this. Firstly, accessing human tissue is difficult and so lots of studies focus on animals instead.

The second reason is technical: until recently we could only examine small pieces of the shuffled molecules, meaning that we had to guess how these fragments were stuck together. This was complicated for big genes like CACNA1C, as they code for many millions of fragments.

We therefore designed a new approach that allowed us to examine full-length CACNA1C molecules for the first time. We used this approach to understand what CACNA1C molecules are present in human brain tissue.

We discovered that the single CACNA1C gene codes for at least 250 subtly different molecules – far more than previously thought. We are now working with collaborators to identify the most important versions and understand what they do.

Although it might initially appear daunting, I believe that this diversity represents an opportunity. For example, because of the complexity of the CACNA1C gene, only a proportion of the molecules it codes for will contain the Timothy Syndrome (TS) mutation in those who carry it.

Therefore, by understanding the processes that generate this diversity of molecules from a single gene, we might be able to find ways to ‘bias’ cells to skip the versions of CACNA1C that contain the damaging mutation.

Although our studies are still at an early stage I am excited about their potential, and look forward to working with the TSA community to try to better understand TS, and to work towards effective treatments.