New models to study Timothy Syndrome

Geoffrey Pitt, Ida and Theo Rossi Distinguished Professor of Medicine, Director of the Cardiovascular Research Institute

At the time of the initial discovery of Timothy Syndrome (TS) in 2004, we already knew that the abnormal calcium channel caused many different health problems.

Over the last 15 years, family led efforts such as the Timothy Syndrome Alliance have provided a platform to share experiences and uncover additional features, some of which continue to puzzle researchers and physicians.

How to address these features medically has been challenging because of the many complex interconnections among different affected body systems and tissues, and because several of these features were not expected to result from abnormal calcium channel function. TS has sent investigators back to the lab to address these surprises.

The Pitt lab at Weill Cornell in New York city set out to create TS animal models. They created mice with either the TS1 mutation or the TS2 mutation, and separately a mouse in which they can activate the abnormal channel in only one or only a subset of organs.

These mouse models provide opportunities to uncover how the abnormal channel contributes to the well-characterised features observed in TS and to explore therapeutic interventions. The various models also allow the investigators to compare the differences between TS1 and TS2.

Further, by creating specialised models in which the effects of the abnormal channel are limited to a single tissue, the scientists can focus on the effects in that tissue, uncomplicated by the influence of the abnormal channel from other tissues. 

Already, the mice have proven instructive. In a research paper published in 2013, the Pitt lab uncovered how the abnormal channel alters development of the facial structure, a feature initially described in children with TS.

In 2019, we shared new results about low blood sugar (hypoglycemia), and the team is now testing which interventions may be effective in preventing or reversing this dangerous condition.

Because the mice display several other features that have been observed in TS children, the mice offer additional opportunities to uncover why these features develop and how they might be addressed. Indeed, most TS features are also present in the mouse models.

In a soon-to-be-published study, however, the Pitt lab shows that the TS1 mice do not have the extra skin between their fingers and/or toes that is often seen in TS1 children.

Nevertheless, the mice have been powerful tools to study TS and may yield future discoveries and therapeutic interventions.

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