Department of Pharmacology and Toxicology
Institute of Pharmacy
University of Innsbruck
Website Nadine Ortner
”De novo CACNA1D variants in neurodevelopmental disease – from bench to bedside”
Mutations that alter the function of voltage-gated Ca2+ channels (Cavs) are implicated in a variety of human diseases. This is not surprising since Cavs are expressed throughout the body, including the central nervous system, and allow tightly controlled Ca2+ influx in response to electrical signals. There is accumulating evidence that gating-modifying de novo variants of CACNA1D, the gene encoding the pore-forming α1 subunit of L-type Cav1.3 Ca2+ channels, cause a neurodevelopmental syndrome with or without endocrine symptoms. The symptomatic spectrum of the so far described 13 patients differs from Cav1.3 loss-of-function (deafness and bradycardia), indicating that these mutations enhance channel activity. This overall gain of channel function renders inhibition of Cav1.3 a potential therapeutic option – a challenge since no isoform-selective inhibitors exist so far. The main research aims of our lab are i) to understand how these genetic variants can cause the broad symptomatic spectrum observed in affected individuals, ii) to study which body systems and brain circuits are affected, and iii) to test therapeutic strategies. In my talk I will give you an overview on our current research, ranging from the biophysical characterization and classification of these variants, to the generation of disease models as well as preclinical treatment attempts.
Host: Matej HOTKA
Contact for questions: Helmut KUBISTA