Phospholamban (PLN) p.Arg14del mutant (PLN-R14del)

Phospholamban (PLN) is a small 52-amino acid transmembrane protein that regulates the activity of the sarco/endoplasmic reticulum calcium ATPase (SERCA2a) in cardiac muscle (Haghighi et al., 2003, PubMed: 12529407). The p.Arg14del (R14del) mutation is a pathogenic deletion of arginine at position 14, which leads to a severe, early-onset form of dilated or arrhythmogenic cardiomyopathy (Remme et al., 2014, PubMed: 24585194). This mutant protein acts through a dominant-negative or toxic gain-of-function mechanism, resulting in chronic inhibition of SERCA2a, impaired calcium handling, and the formation of perinuclear protein aggregates (Karakikes et al., 2015, PubMed: 25866243). Therapeutic strategies targeting the PLN-R14del allele focus on reducing the expression of the mutant protein using antisense oligonucleotides (ASOs) or RNA interference, as well as gene therapy approaches to restore SERCA2a function or provide a healthy copy of the PLN gene (Ionis Pharmaceuticals, 2022; Tenaya Therapeutics, 2023). These precision medicine strategies represent a significant shift from traditional heart failure treatments by addressing the underlying genetic cause of the disease.

Other names

PLN p.Arg14delPhospholamban arginine 14 deletionR14del-PLNPLN c.40_42delAGAMutant PLN-R14del

Allele-specific antisense-mediated mRNA degradation and AAV-mediated gene replacement or SERCA2a activation.