Grant: Project Grant

In the heart, muscle contraction is triggered by the release of calcium from the internal calcium stores through the calcium release channel, called the ryanodine receptor type 2 (RyR2). It has been well established that enhanced RyR2 activity as a result of gain-of-function RyR2 varuants can lead to irregular heart rhythm and sudden death. Recently, our research team discovered that RyR2 loss-of-function variants can cause a previously unknown heat disease we named RyR2 calcium release deficiency syndrome (CRDS). A horrifying feature of CRDS is that patients having CRDS usually show no obvious sign of heart disease on standard clinical testing, but often suffer from sudden death as the first symptom. These catastrophic events clearly demonstrate that our understanding of CRDS is far from complete. Therefore, there is a urgent need to better understand this newly discovered heart disease and to develop a diagnostic test for CRDS in order to prevent these tragic events and save lives. The objective of this research proposal is to explore the clinical features, mechanisms, and diagnosis of CRDS. To achieve this goal, we propose to identify and characterize novel RyR2 loss-of-function variants and their associated heart defects, to validate and characterize a new form of CRDS associated with cardiomyopathy, to define the initial event in heart rhythm that triggers sudden death, and to develop a novel diagnostic test for CRDS. We have assembled an international collaborative team with multidisciplinary and complementary experience and expertise in both clinical and basic investigation of heart rhythm disorders. We expect that our proposed studies will reveal novel insights into the manifestation and mechanism of CRDS. We also expect to establish the first non-life-threatening clinical test for the diagnosis of CRDS.