[Distribution characteristics of PKP2 non-synonymous variations in protein domain and genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy].

Objective

Investigate the distribution characteristics of plakophilin 2 (PKP2) variants in the protein structural domains and the relationship between genotypes and phenotypes in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).

Methods

By searching the Human Gene Mutation Database, ClinVar, PubMed and Embase databases, all reported PKP2 variants were collected. These variants were classified based on mutation types, ultimately including non-synonymous single nucleotide variations (nsSNVs) associated with ARVC. Simultaneously, topology information of the PKP2 protein was retrieved from the Uniprot database, and PKP2 nsSNVs were categorized according to the protein's structural domains. The pathogenicity of PKP2 nsSNVs was assessed using the InterVar software, and the distribution of pathogenic classifications in different structural domains was explored. Hotspot variants were selected from PKP2 nsSNVs, and their distribution characteristics in structural domains were analyzed. Finally, R software was employed to analyze the overall distribution patterns of PKP2 total variants, pathogenic or likely pathogenic variants and hotspot variants in protein structural domains, and the correlation between PKP2 variants and ARVC clinical phenotypes.

Results

This study collected a total of 1 358 reported PKP2 variants, which included 497 nsSNVs associated with ARVC. The PKP2 nsSNVs associated with ARVC were significantly enriched in the Arm1, Arm2, Arm3, and Arm7 regions of the protein structure. Additionally, 55 pathogenic or likely pathogenic variants were enriched in the Arm3 and Arm5. There were a total of 179 hotspot variants, and their pathogenic risks did not show significant differences compared to other nsSN Vs. Variants located in the Arm1 domain were more prone to ventricular premature contractions, while patients with variants in the Arm4 were more likely to exhibit myocardial fibrofatty changes. Patients with variants in the Region1 were more susceptible to ventricular tachycardia (all P<0.05).

Conclusion

The PKP2 nsSNVs associated with ARVC are enriched in the Arm1, Arm2, Arm3, and Arm7 structural domains, with a higher proportion of pathogenic or likely pathogenic variants in the Arm3 and Arm5 domains. Moreover, Region 1 significantly increases the risk of ventricular arrhythmia among ARVC patients.