Phospholamban (Arg14 deletion) (PLN-R14del) (PLN-R14del)

Phospholamban (PLN) is a 52-amino acid integral membrane protein that regulates the sarcoplasmic reticulum calcium ATPase (SERCA2a) in cardiac myocytes, thereby controlling calcium reuptake and muscle relaxation (UniProt P26678). The PLN-R14del mutant allele refers to a specific pathogenic deletion of the arginine residue at position 14, which is a critical phosphorylation site for protein kinase A (PKA) (Haghighi et al., 2003). This mutation leads to a toxic gain-of-function where the mutant protein chronically inhibits SERCA2a and forms perinuclear aggregates, disrupting calcium homeostasis and cellular proteostasis (Eijgenraam et al., 2020). Clinically, the R14del mutation is a founder mutation prevalent in the Netherlands and is associated with a high risk of dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM), often leading to sudden cardiac death (van der Zwaag et al., 2012). Therapeutic development focuses on allele-specific silencing using antisense oligonucleotides (ASOs) or gene replacement therapies like TN-401 to restore functional PLN levels and SERCA2a activity (Tenaya Therapeutics, 2023). These interventions aim to halt or reverse the progression of heart failure and reduce the incidence of life-threatening arrhythmias in mutation carriers.

Other names

PLN p.Arg14delPhospholamban Arg14 deletionR14del-PLNPLN-R14del

AAV-mediated gene replacement therapy and antisense-mediated knockdown of mutant mRNA