Key result
Truncating PKP2 mutations in arrhythmogenic cardiomyopathy were associated with PKP2 transcript and protein levels reduced to approximately 50% in both myocardium and keratinocytes.
Observational (n=71)
Truncating PKP2 mutations in arrhythmogenic cardiomyopathy cause protein haploinsufficiency that is detectable in both myocardial tissue and epidermal keratinocytes, suggesting a shared pathogenic mechanism.
May support noninvasive keratinocyte assessment of PKP2 expression; hypothesis-generating for arrhythmogenic cardiomyopathy mechanisms and requires prospective validation.
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The disease is most often caused by mutations in the desmosomal gene for plakophilin-2 (PKP2), which is expressed in both myocardial and epidermal tissue. This study aimed to investigate protein expression in myocardial tissue of patients with AC carrying PKP2 mutations and elucidate whether keratinocytes of the same individuals exhibited a similar pattern of protein expression. METHODS AND RESULTS: Direct sequencing of 5 AC genes in 71 unrelated patients with AC identified 10 different PKP2 mutations in 12 index patients. One patient, heterozygous for a PKP2 nonsense mutation, developed severe heart failure and underwent cardiac transplantation. Western blotting and immunohistochemistry of the explanted heart showed a significant decrease in PKP2 protein expression without detectable amounts of truncated PKP2 protein. Cultured keratinocytes of the patient showed a similar reduction in PKP2 protein expression. Nine additional PKP2 mutations were investigated in both cultured keratinocytes and endomyocardial biopsies from affected individuals. It was evident that PKP2 mutations introducing a premature termination codon in the reading frame were associated with PKP2 transcript and protein levels reduced to ≈50%, whereas a missense variant did not seem to affect the amount of PKP2 protein. CONCLUSIONS: The results of this study showed that truncating PKP2 mutations in AC are associated with low expression of the mutant allele and that the myocardial protein expression of PKP2 is mirrored in keratinocytes. These findings indicate that PKP2 haploinsufficiency contributes to pathogenesis in AC.
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Rasmussen et al. (2014) conducted an observational in Arrhythmogenic cardiomyopathy (n=71). Truncating PKP2 mutations vs. Missense variant was evaluated on PKP2 transcript and protein levels. Truncating PKP2 mutations in arrhythmogenic cardiomyopathy were associated with PKP2 transcript and protein levels reduced to approximately 50% in both myocardium and keratinocytes.
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