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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by progressive fibrofatty replacement of the right ventricular myocardium, malignant ventricular arrhythmias, and risk of sudden cardiac death. Plakophilin-2 (PKP2), encoded by HGNC:9024, is a critical desmosomal protein ensuring mechanical and electrical coupling at cardiomyocyte intercalated discs. Heterozygous PKP2 mutations are the most frequently detected genetic lesions in ARVC, accounting for up to 40% of familial cases across diverse populations.
Genetic evidence supporting PKP2 in ARVC comes from multiple large cohorts. In a study of 120 unrelated ARVC probands, heterozygous PKP2 mutations were identified in 32 of 120 probands (PMID:15489853), demonstrating autosomal dominant inheritance with incomplete penetrance. Family-based screening in a Danish ARVC cohort confirmed that 7 of 65 patients carried PKP2 variants, often in conjunction with other desmosomal gene defects, highlighting allelic heterogeneity and digenic contributions (PMID:20864495).
Segregation analysis in a multidisciplinary case series further corroborates PKP2 pathogenicity. Screening of 117 first‐degree relatives of 44 ARVC probands revealed 29 additional affected relatives who carried familial PKP2 mutations, confirming co‐segregation of desmosomal defects with disease phenotype (PMID:30126789).
The PKP2 variant spectrum includes frameshift, nonsense, splice‐site, and missense mutations distributed throughout the armadillo repeat domains. A recurrent founder truncating mutation, c.368G>A (p.Trp123Ter), has been reported in a three‐generation family with variable expressivity of ARVC, underscoring the importance of truncating alleles in disease causation (PMID:22035158).
Functional studies illuminate the molecular mechanism of PKP2-mediated ARVC. Patient‐derived iPSC‐cardiomyocytes harboring PKP2 mutations display reduced cell‐surface localization of desmosomal proteins, altered intercalated disc ultrastructure, and increased lipid accumulation, faithfully recapitulating ARVC pathology in vitro (PMID:22798562). In murine models, cardiac‐specific Pkp2 deletion leads to loss of nuclear envelope integrity, DNA damage, and heightened oxidant production, linking PKP2 deficiency to arrhythmogenic substrate formation (PMID:35959657).
Copy number variation analyses have identified heterozygous PKP2 exon deletions in ARVC families lacking point mutations, emphasizing the necessity of CNV screening in comprehensive genetic diagnostics (PMID:28431057). Gene therapy approaches using AAV‐mediated PKP2 delivery in murine knockout models have arrested ARVC progression and normalized arrhythmia burden, offering preclinical proof‐of‐concept for targeted interventions (PMID:38288614).
PKP2 is definitively established as the predominant ARVC gene, with autosomal dominant inheritance and a broad mutation spectrum. Genetic testing of PKP2, including sequencing and CNV analysis, is essential for diagnosis, family screening, and risk stratification, enabling early intervention to prevent malignant arrhythmias and sudden cardiac death.
Gene–Disease AssociationDefinitiveOver 120 unrelated probands and multi-generational families with segregation and functional concordance Genetic EvidenceStrong32 probands with PKP2 mutations in an ARVC cohort; extensive cascade screening in relatives Functional EvidenceStrongiPSC and murine models recapitulate ARVC phenotype; gene therapy rescue demonstrated |