Pkp2-KO Mouse

PKP2, or plakophilin-2, is a component of the desmosome complex, playing a crucial role in cell-cell adhesion [2]. The desmosome is important for maintaining the integrity of tissues, especially in the heart where proper cell-cell adhesion is vital for normal cardiac function.

In arrhythmogenic cardiomyopathy (ACM), which is characterized by lethal arrhythmias and sudden cardiac death, PKP2 is the most frequently affected gene. AAV-mediated delivery of PKP2 in PKP2 mutant induced pluripotent stem cell-derived cardiomyocytes restored cardiac PKP2 levels and those of other junctional proteins, improved sodium conduction, enhanced contractile function, and normalized contraction kinetics. In vivo, treating heterozygous Pkp2c.1755delA knock-in mice with AAV9-PKP2 corroborated the recovery of desmosomal integrity and cardiac function, and long-term treatment prevented cardiac dysfunction in 12-month-old Pkp2c.1755delA/WT mice [1]. In addition, adult hearts deficient in PKP2 show loss of nuclear envelope integrity, increased oxidant production, and DNA damage, key substrates in the molecular pathology of ACM [3].

In summary, PKP2 is essential for cell-cell adhesion, especially in the heart. Gene-knockout and related mouse models have revealed its critical role in arrhythmogenic cardiomyopathy, showing that restoring PKP2 can potentially rescue the arrhythmic substrate and cardiac function. These findings encourage the exploration of PKP2 gene therapy for ACM patients with PKP2 haploinsufficiency [1].

References:

1. Kyriakopoulou, Eirini, Versteeg, Danielle, de Ruiter, Hesther, Giacca, Mauro, van Rooij, Eva. 2023. Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy. In Nature cardiovascular research, 2, 1262-1276. doi:10.1038/s44161-023-00378-9. https://pubmed.ncbi.nlm.nih.gov/38665939/

2. Novelli, Valeria, Malkani, Kabir, Cerrone, Marina. 2018. Pleiotropic Phenotypes Associated With PKP2 Variants. In Frontiers in cardiovascular medicine, 5, 184. doi:10.3389/fcvm.2018.00184. https://pubmed.ncbi.nlm.nih.gov/30619891/

3. Pérez-Hernández, Marta, van Opbergen, Chantal J M, Bagwan, Navratan, Delmar, Mario, Lundby, Alicia. 2022. Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC. In Circulation, 146, 851-867. doi:10.1161/CIRCULATIONAHA.122.060454. https://pubmed.ncbi.nlm.nih.gov/35959657/