The link between mutations in CACNA1C and Timothy syndrome symptoms

Gemma Wilkinson, Research student, Cardiff University

Patients with Timothy syndrome often have developmental delays, including autism spectrum disorder and intellectual disability. My research aims to find how mutations in CACNA1C lead to these symptoms.

To do this, I am using cells from patients with Atypical Timothy Syndrome. We are able to take a blood sample from patients and turn the blood cells into stem cells, which we can then grow into brain cells (neurons) to study.

CACNA1C is an important gene during brain development, so I am investigating the ability of patient cells to become neurons and the different types of cells that are produced.

The two images below show the cells throughout the differentiation process.

When the cells first start to produce neurons, they grow outward from the large clump of cells in the centre of the image.

Microscopic cells - day 21
The cells at Day 21
Microscopic cells - day 30
The cells at Day 30

By Day 30, you can see a lot more neurons, and they have long processes, which is how they connect to each other to signal.

Additionally, once we have produced neurons, we can measure their electrical activity to see how well connected they are, as patients with autism spectrum disorder often show alterations in brain connectivity and activity.

Neurons usually form networks with regular synchronised bursts of activity. However, when the activity of the Atypical Timothy Syndrome line was recorded, it showed alterations in this activity; synchronised bursts occurred less often and less regularly.

As mutations in Timothy Syndrome cause prolonged opening of the calcium channel Cav1.2, we next looked at the effect of blocking this channel using a drug called diltiazem. Addition of diltiazem rescued neuronal activity in the Atypical Timothy Syndrome neurons as shown in the image below.

In the future, we aim to compare the effects of different Timothy Syndrome mutations on neuronal activity to identify similarities and differences between patients and possible treatments to rescue these changes.

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