Understanding CPVT pathogenic mechanisms based on mutation location within RyR2: towards personalized medicine?

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder that typically presents as syncope or sudden cardiac death (SCD), most often in children and young adults during physical or emotional stress. The heart shows no signs of structural cardiac disease. This disorder belongs to the so‐called channelopathies. There are several types of CPVT, depending on the affected gene, with inheritance patterns that can be either dominant (most cases) or recessive.

Patients diagnosed with CPVT are generally treated with β‐adrenergic blockers (preferably nadolol or propranolol) to avoid stress‐induced episodes. However, this treatment is sometimes insufficient, and additional antiarrhythmic agents are added, mainly flecainide, a sodium channel blocker that also acts directly on the cardiac ryanodine receptor (RyR2). Since the introduction of flecainide on top of β‐blockers, implantable defibrillator‐cardioverter devices are rarely needed. Some concern remains, however, as device discharges – whether appropriate or not – may exacerbate the catecholaminergic drive and worsen the arrhythmic burden, potentially leading to arrhythmic storm and SCD.

The most common form, CPVT1, is associated with mutations in the ryanodine receptor type 2 (RyR2), the channel through which Ca²⁺ is released from the sarcoplasmic reticulum into the cytosol. These are typically missense mutations, where an amino acid (aa) is substituted by another, altering the channel's function. Identified mutations cluster in major regions of the protein: the N‐terminal (aa 44–466), central (aa 2246–2534), and C‐terminal (aa 3778–4959, separated in two clusters) domains (Fig. 1). Even if some mutations appear to lie far apart in the primary structure, they may be very close in the tertiary structure. In this sense, Uchinoumi et al. (2026) showed that the first 220 aa in the N‐terminal portion of RyR2 interact with the region 2300–2500 in the central domain that stabilizes the RyR2 closed state, a mechanism referred to as ‘zipping.’ Furthermore, in the zipped configuration, calmodulin (CaM) binding to the channel is enhanced. A domain peptide, DPc10‐corresponding to the 2460–2495 amino acid sequence in the central domain‐interacts with the N‐terminal portion when the RyR2 is unzipped, preventing the zipping interaction and reducing CaM binding, thereby rendering the RyR2 leaky. Dantrolene exerts the opposite effect, promoting the zipped conformation.

Figure 1. Schematic representation of RyR2 domains and CPVT hotspots.

Top: Linear sequence of the RyR2 protein with different domains highlighted in colour, in the following order: N‐terminal domain, SPYR domains, junctional solenoid domain, bridging solenoid domains, shell‐core linker domain, core solenoid, thumb and forefingers domain, transmembrane domain, and C‐terminal domain (including the pore region). CPVT‐associated hotspots are indicated in black, representing regions where the majority of pathogenic variants are concentrated. Sequences involved in the proposed zipping mechanism are shown in grey, located within the N‐terminal and central regions. A white section within the grey central domain corresponds to the DPC10 amino acid sequence. Bottom: Approximate localization of these domains within a single RyR2 monomer, shown in the context of the homotetramer in top view (left) and side view (right).

Regardless of the exact mechanism, the prevailing model of arrhythmogenesis involves spontaneous diastolic Ca²⁺ release in ventricular cardiomyocytes. This leads to Ca²⁺ waves – Ca²⁺ sparks triggered by clusters of RyR2 that propagate throughout the cell, amplifying Ca²⁺ release. The resulting increase in intracellular diastolic [Ca²⁺] is cleared via the Na⁺/Ca²⁺ exchanger, which extrudes one Ca²⁺ ion in exchange for three Na⁺ ions. This generates an inward depolarizing current that may induce a delayed afterdepolarization, which can trigger an ectopic action potential.

Although this general mechanism is widely accepted, each RyR2 mutation may result in a distinct molecular alteration. For a mutation to be pathogenic, it must alter RyR2 function under stress. Some, if not most, mutations also impact basal channel activity, though not enough to cause arrhythmias. Most mutations are classified as gain‐of‐function, although some loss‐of‐function variants have been reported.

Elucidating these mutation‐specific mechanisms is essential for advancing personalized treatment approaches. While over 200 RyR2 mutations have been identified, it is unlikely that each entails a unique pathophysiological mechanism. Mutations close to each other in the primary or tertiary structure may share similar molecular consequences, offering the potential to stratify treatment based on mutational clusters.

Several mutation‐specific mechanisms have been identified in mouse models depending on their locations, as described in the following examples.

C‐terminal domain

The p.R4496C mutation is associated with increased Ca²⁺ sensitivity (Fernandez‐Velasco et al., 2009). In contrast, the p.A4860G mutation within the pore results in loss of function (Zhao et al., 2015).

Central domain

The p.R2474S mutation disrupts the zipping–unzipping interaction between the N‐terminal and central domains (Uchinoumi et al., 1998). Others reported that this mutation affects FKBP12.6 binding to RyR2, destabilizing it (Lehnart et al., 2008).

N‐terminal domain

The p.R420Q mutation interferes with inter‐domain interactions, particularly with the core solenoid (Yin et al., 2021), impairing RyR2 closing.

Some CPVT variants have also been identified outside the hotspots, with distinct mechanisms, such as p.D3291V, which impairs cAMP response (Blancard et al., 2021).

In this issue of The Journal of Physiology, Uchinuomi et al. (2026) investigate how three CPVT‐linked RyR2 mutations – one in each region – affect channel function, namely the p.R176Q (N‐terminal), the p.R2474S (central domain), and the p.R4496C (C‐terminal domain). Using knock‐in mouse models and an elegant approach with permeabilized cardiomyocytes and FRET imaging, the authors show that at baseline, none of these mutations altered CaM affinity for RyR2 or the ‘unzipped’ state. However, PKA activation induced a pathological RyR2 conformation marked by reduced CaM binding, increased access of the DPc10 peptide, and enhanced diastolic Ca²⁺ leak only in the N‐terminal and central domain variants (without altering FKBP12.6‐RyR2 binding). These alterations suggest that these mutations favour the ‘unzipped’ configuration only following PKA activation. In contrast, the p.R4496C variant displays increased Ca²⁺ leak upon PKA activation but without changes in CaM or DPc10 binding, indicating a distinct pathological mechanism. Notably, dantrolene reversed the pathological conformation and Ca²⁺ leak in the N‐terminal and central variants but had no effect on p.R4496C.

These findings underscore that not all CPVT‐linked RyR2 mutations behave similarly at the molecular level, which has direct implications for therapy. Variants in the N‐terminal and central domains may respond to treatments that stabilize RyR2 conformation (e.g. dantrolene or CaM modulators), while C‐terminal mutations like p.R4496C may require alternative strategies, such as targeting calcium sensitivity or downstream signalling pathways.

All in all, current knowledge has been further expanded by Uchinoumi and colleagues, supporting the view that CPVT management needs a mutation‐specific approach in the era of personalized medicine. Advances in the pursuit of precision medicine in inherited arrhythmia syndromes will likely make this a reality in everyday clinical practice.

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Competing interests

None of the authors has any conflicts of interests.

Author contributions

All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

This work was funded by Inserm and University Paris‐Saclay, and grants from ANR (ANR‐19‐CE14‐0031‐01, ANR‐23‐CE14‐0009‐02, ANR‐24‐CE14‐2131‐01).

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