Voltage-gated calcium channels are proteins embedded in the cell membrane, regulating the influx of calcium ions into cells. They are found in nerve, heart, muscle, and endocrine gland cells, and control various physiological processes — for example, the release of neurotransmitters or hormones. While many types of these channels and their links to specific diseases have already been well studied, much less is known about the CaV1.3 subtype and its blueprint gene, CACNA1D.
“About 25 years ago, researchers at the University of Innsbruck switched off the CACNA1D gene in mice. The animals developed hearing loss and mild heart dysfunction, and this was later confirmed in humans with genetic loss-of-function mutations in CACNA1D,” explains Nadine Ortner, who now leads the new research group within the Department of Pharmacology and Toxicology. But that was only the beginning of the story: “Twelve years ago, the first reports emerged of two children carrying mutations in CACNA1D who not only showed brain development disorders but also hormone-related problems. We were completely surprised at the time — no one had made the connection yet,” Ortner recalls.
Rare mutations provide insights into basic biomedical mechanisms
Today, research conditions have changed dramatically. Gene mutations are now easier to detect thanks to advances in sequencing technology, which is also increasingly used for diagnostic purposes. Although mutations in CACNA1D remain rare in patients with brain development disorders, the number of diagnoses is steadily rising — partly due to the growing awareness generated by published studies and case reports.
“Different pathogenic variants lead to different functional changes of CaV1.3 calcium channels — and these, in turn, result in very diverse clinical symptoms,” says Ortner. The range of symptoms is broad and spans from mild intellectual impairments or forms of autism spectrum disorder to severe developmental delays, self-injurious behavior, hormonal imbalances, and daily epileptic seizures. “Our goal is to better understand how exactly these specific functional changes give rise to particular symptoms.”
Diseases associated with CACNA1D belong to the group of so-called “rare diseases” — conditions that are often under-researched and leave patients and their families without sufficient support. This is exactly what the newly established research group wants to change. The team brings together expertise from pharmacy, stem cell research, genomics, and computer science. In addition to Nadine Ortner, the team includes Frank Oliver Stefan Edenhofer and Christopher Esk from the Institute of Molecular Biology, as well as Petronel Tuluc and Stefanie Geisler from the Institute of Pharmacy. Each of them investigates CACNA1D from a different scientific angle.
The researchers’ goal is not only to create a comprehensive picture of this particular rare disease but also to contribute to a better understanding of other so-called “calcium channelopathies.” Importantly, they closely involve patients and their families in their research. “We work in close contact with a patient organized group and stay in constant exchange with those affected and their physicians,” says Ortner. “This gives us valuable insight into their everyday lives — and in turn, we share our research findings with them.”
A holistic approach using multiple model systems
The research group, which was officially launched on May 12, is investigating the malfunctions of CaV1.3 caused by mutations of CACNA1D in different model systems tailored to the expertise of the respective researchers:
Nadine Ortner is studying the effects of a mild CACNA1D mutation in a specially developed mouse model, where she has already observed some changes — even at the cellular level — that resemble the symptoms found in human patients.
Stem cell expert Frank Edenhofer has developed an inducible pluripotent stem cell line capable of generating different specialized cell types from patient-derived cells. Christopher Esk is using these and newly generated patient stem cells to create so-called brain organoids — three-dimensional structures that mimic aspects of the human brain, allowing the study of early brain development disorders.
Stefanie Geisler contributes her expertise in electrophysiology, investigating disturbances in the electrochemical communication of nerve cells derived from patient stem cells in high-resolution detail. Petronel Tuluc complements the team with his focus on hormone-producing cells and is developing a computer model that integrates data from the different subprojects. This model could eventually replace some experiments and help streamline research and drug development.
“We’re systematically bringing together these different model systems to investigate the mechanisms of disease and potential therapeutic approaches — something that has never been done in this way for channelopathies,” says Nadine Ortner. “That’s why our experimental strategy and the knowledge we hope to gain could also be relevant for other diseases involving ion channels.”
Even if the research findings won’t directly benefit current patients, Ortner emphasizes the importance of their involvement: “Although the expected research results will probably no longer directly benefit the affected individuals who are currently providing support, we communicate in our regular exchange that their participation will be of significant value to future patients.”