“Ryanopathies” and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?

Abstract

The regulation of intracellular calcium (Ca2+) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients’ cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient’s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.

Calcium Handling in Inherited Cardiac Diseases: A Focus on Catecholaminergic Polymorphic Ventricular Tachycardia and Hypertrophic Cardiomyopathy

“…Indeed, these domains are implicated in channel activation and gating. A potential link between mutation localization and phenotype severity has been emphasized [ 18 , 21 ]. Therefore, mutations located in the C-terminus of the RYR2 protein have been correlated with sudden death during sleep [ 22 ].…”

Cardiac side effects of RNA‐based SARS‐CoV‐2 vaccines: Hidden cardiotoxic effects of mRNA‐1273 and BNT162b2 on ventricular myocyte function and structure

“…Numerous papers have identified mutation‐related RyR2 dysfunction as a causal agent of arrhythmias, ventricular tachycardia, and sudden cardiac death (Jóna & Nánási, 2006; Seidlmayer et al, 2018; Sleiman et al, 2021; Thomas et al, 2005). RyR2‐induced cardiomyopathies may further be characterized by a structurally remodelled myocardium, but our histological findings did not provide evidence of disruption of sarcomeric transverse striation, so that the described symptomatology 48 h after application is in all likelihood purely functional in causation (Benitah et al, 2021).…”

How Functional Genomics Can Keep Pace With VUS Identification

“…They make up the largest human channels (>2-MDa) and RyR2 is primarily expressed in cardiac muscle ( Figure 1D ). However, given their intracellular location and function, they are not amenable for automated patch clamp studies nor the other HTP measurements discussed ( 90 ). One attempt used HEK 293 cells stably expressing skeletal muscle RyR1 for time lapse [Ca 2+ ] ER measurements in a 96 well format ( 91 ).…”

“…Finally, variants can exert their effects through other mechanisms such as β-adrenergic stimulation such as KCNQ1, KCNJ2 ( 111 ) and RYR2-associated CPVT ( 90 ). For example, truncating TTN variants (the most common variants) showed a reduced response to β-adrenergic stress among other dysfunctions in an iPS-CM model ( 112 ).…”