Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis.
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 epiderma...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Lippincott Williams and Wilkins
2014
|
| _version_ | 1797074168360992768 |
|---|---|
| author | Rasmussen, T Nissen, P Palmfeldt, J Gehmlich, K Dalager, S Jensen, U Kim, W Heickendorff, L Mølgaard, H Jensen, H Baandrup, U Bross, P Mogensen, J |
| author_facet | Rasmussen, T Nissen, P Palmfeldt, J Gehmlich, K Dalager, S Jensen, U Kim, W Heickendorff, L Mølgaard, H Jensen, H Baandrup, U Bross, P Mogensen, J |
| author_sort | Rasmussen, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:32:27Z |
| format | Journal article |
| id | oxford-uuid:6c86b0f2-170e-419d-9379-e048935811ec |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:32:27Z |
| publishDate | 2014 |
| publisher | Lippincott Williams and Wilkins |
| record_format | dspace |
| spelling | oxford-uuid:6c86b0f2-170e-419d-9379-e048935811ec2022-03-26T19:11:26ZTruncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6c86b0f2-170e-419d-9379-e048935811ecEnglishSymplectic Elements at OxfordLippincott Williams and Wilkins2014Rasmussen, TNissen, PPalmfeldt, JGehmlich, KDalager, SJensen, UKim, WHeickendorff, LMølgaard, HJensen, HBaandrup, UBross, PMogensen, JBACKGROUND: 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. |
| spellingShingle | Rasmussen, T Nissen, P Palmfeldt, J Gehmlich, K Dalager, S Jensen, U Kim, W Heickendorff, L Mølgaard, H Jensen, H Baandrup, U Bross, P Mogensen, J Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. |
| title | Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. |
| title_full | Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. |
| title_fullStr | Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. |
| title_full_unstemmed | Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. |
| title_short | Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. |
| title_sort | truncating plakophilin 2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis |
| work_keys_str_mv | AT rasmussent truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT nissenp truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT palmfeldtj truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT gehmlichk truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT dalagers truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT jensenu truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT kimw truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT heickendorffl truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT mølgaardh truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT jensenh truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT baandrupu truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT brossp truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis AT mogensenj truncatingplakophilin2mutationsinarrhythmogeniccardiomyopathyareassociatedwithproteinhaploinsufficiencyinbothmyocardiumandepidermis |