Pln, short for phospholamban, is a key modulator of Ca2+-homeostasis. It inhibits sarcoplasmic reticulum (SR) calcium-ATPase (SERCA2a), thereby regulating cardiac contractility. Calcium cycling regulated by Pln is crucial for normal heart function [2].

The p.Arg14del variant of the Pln gene (PLN-R14del) causes cardiomyopathy, leading to severe heart failure in humans. In a PLN-R14del mouse model, which mimics human disease characteristics, DWORF overexpression delays cardiac fibrosis, heart failure, and extends lifespan by reducing abnormal sarcoplasmic reticulum clusters. This indicates that abnormal S/ER organization in PLN-R14del cardiomyopathy contributes to cardiac dysfunction [1]. Additionally, in transgenic mice with the PLN-R14del+/- mutation, there is hyperdynamic Ca2+ handling, suggesting a loss of SERCA2a inhibition by PLN, and depressed energy metabolism, pointing to early metabolic stress involvement in the pathogenesis of this arrhythmogenic cardiomyopathy model [3].

In conclusion, Pln is essential for regulating calcium cycling and cardiac contractility. Studies using mouse models, especially those with the PLN-R14del mutation, have revealed its role in cardiomyopathy development. These models contribute significantly to understanding the mechanisms underlying heart failure and related cardiac diseases associated with Pln genetic variants.

References:

1. Stege, Nienke M, Eijgenraam, Tim R, Oliveira Nunes Teixeira, Vivian, de Boer, Rudolf A, Silljé, Herman H W. 2023. DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters. In Circulation research, 133, 1006-1021. doi:10.1161/CIRCRESAHA.123.323304. https://pubmed.ncbi.nlm.nih.gov/37955153/

2. Vafiadaki, Elizabeth, Haghighi, Kobra, Arvanitis, Demetrios A, Kranias, Evangelia G, Sanoudou, Despina. 2022. Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired Ca2+ Handling and Arrhythmogenesis. In International journal of molecular sciences, 23, . doi:10.3390/ijms23136947. https://pubmed.ncbi.nlm.nih.gov/35805951/

3. Maniezzi, Claudia, Eskandr, Marem, Florindi, Chiara, Lodola, Francesco, Zaza, Antonio. 2024. Early consequences of the phospholamban mutation PLN-R14del+/- in a transgenic mouse model. In Acta physiologica (Oxford, England), 240, e14082. doi:10.1111/apha.14082. https://pubmed.ncbi.nlm.nih.gov/38214033/