Phospholamban p.Arg14del (PLN-R14del)

The PLN-R14del allele is a specific pathogenic variant of the phospholamban (PLN) gene, characterized by the deletion of arginine at position 14 in the 52-amino acid protein. Under physiological conditions, phospholamban is a critical micropeptide that regulates the sarco/endoplasmic reticulum calcium-ATPase (SERCA2a), thereby modulating cardiac contraction and relaxation (Haghighi et al., 2006; MacLennan & Kranias, 2003). The R14del mutation, a prevalent founder mutation in the Netherlands, causes the protein to become a 'super-inhibitor' of SERCA2a or form toxic perinuclear aggregates that disrupt intracellular calcium homeostasis and trigger the unfolded protein response (UPR) (Eijgenraam et al., 2024; Vafiadaki et al., 2023). This leads to severe inherited cardiomyopathies, including Dilated Cardiomyopathy (DCM) and Arrhythmogenic Cardiomyopathy (ACM), which often manifest as progressive heart failure or sudden cardiac death (van der Zwaag et al., 2012). Current therapeutic development focuses on precision medicine approaches, such as allele-specific antisense oligonucleotides (ASOs) and CRISPR-Cas9 gene editing (TNGE101), to specifically suppress the mutant allele and restore normal cardiac function (Grote Beverborg et al., 2022; Tenaya Therapeutics, 2025). As a therapeutic target, PLN-R14del represents a high-priority site for gene-modifying therapies aimed at addressing the root cause of genetic heart failure.

Other names

p.Arg14del mutationPLN p.R14delPLN-R14ΔPhospholamban arginine 14 deletionPhospholamban (PLN) R14del allele

The PLN-R14del allele is primarily targeted through allele-specific silencing using antisense oligonucleotides (ASOs) or RNA interference (siRNA) to reduce mutant protein levels. It is also a candidate for CRISPR-Cas9-mediated gene editing to correct or disrupt the mutant sequence. Secondary mechanisms include activating the unfolded protein response (UPR) to clear toxic aggregates or pharmacological activation of SERCA2a to restore calcium handling.