Multi-system study of pathogenic CACNA1D variants

Calcium is a vital signaling molecule controlling many body functions including hormone release, muscle contraction and brain function. This is also evident from a large number of disease-associated genetic variants in genes that encode calcium channels, which are gateways in cellular membranes that let calcium ions enter the cell in a strictly regulated manner. Recently, several genetic mutations in the Cav1.3 calcium channel gene CACNA1D have been found in patients with broad neurodevelopmental disorders and hormonal dysregulation. These changes of the genetic CACNA1D sequence induce complex and mutation-specific changes in how Cav1.3 channels work. With increasing numbers of genetic variants and cases it becomes evident that the symptoms of different patients vary greatly, and we think that this is the consequence of the diverse functional changes of individual CACNA1D gene mutations. But how these gating profiles translate into body dysfunction and symptoms is not yet understood. Here we assembled a diverse consortium to bring together outstanding expertise in the field of calcium channel biology, pharmacology, gene engineering, stem cell research and computer modeling to tackle this important health question. This interdisciplinary approach will allow us to study how distinct CACNA1D variants affect different endocrine and neuronal types of cells, which likely underlies the variability of the disease manifestation. We will establish and use a broad range of model systems, including computer models of cellular firing patterns, human endocrine cell lines, inducible pluripotent stem cells that can be differentiated in various cell types and brain organoids, as well as in vivo mouse models. Furthermore, this novel and unique experimental platform will enable us to test various potential therapeutic strategies, which are urgently required to attenuate the symptomatic burden of affected patients. Altogether, our work will provide a comprehensive picture of the disease-causing mechanisms associated with CACNA1D variants, unravel how distinct functional patterns link to specific symptomatic pictures (genotype-phenotype correlation), and whether pharmacological treatment that directly targets this calcium channel can help to attenuate or even reverse some of the symptoms. Our ultimate goal is to provide solid experimental evidence that can facilitate clinical-decision making, set the basis for the development of novel personalized treatment strategies and improve the life quality of affected individuals.