Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility
Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC), with skin manifestations, has been associated with mutations in JUP encoding plakoglobin. Genotype–phenotype correlations regarding the penetrance of cardiac involvement, and age of onset have not been well established. We examined a c...
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2020
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oai:doaj.org-article:ab057a9d7d3946ec9f202a73bd59378c2021-12-02T11:43:58ZArrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility10.1038/s41598-020-78344-92045-2322https://doaj.org/article/ab057a9d7d3946ec9f202a73bd59378c2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78344-9https://doaj.org/toc/2045-2322Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC), with skin manifestations, has been associated with mutations in JUP encoding plakoglobin. Genotype–phenotype correlations regarding the penetrance of cardiac involvement, and age of onset have not been well established. We examined a cohort of 362 families with skin fragility to screen for genetic mutations with next-generation sequencing-based methods. In two unrelated families, a previously unreported biallelic mutation, JUP: c.201delC; p.Ser68Alafs*92, was disclosed. The consequences of this mutation were determined by expression profiling both at tissue and ultrastructural levels, and the patients were evaluated by cardiac and cutaneous work-up. Whole-transcriptome sequencing by RNA-Seq revealed JUP as the most down-regulated gene among 21 skin fragility-associated genes. Immunofluorescence showed the lack of plakoglobin in the epidermis. Two probands, 2.5 and 22-year-old, with the same homozygous mutation, allowed us to study the cross-sectional progression of cardiac involvements in relation to age. The older patient had anterior T wave inversions, prolonged terminal activation duration (TAD), and RV enlargement by echocardiogram, and together with JUP mutation met definite ARVC diagnosis. The younger patient had no evidence of cardiac disease, but met possible ARVC diagnosis with one major criterion (the JUP mutation). In conclusion, we identified the same biallelic homozygous JUP mutation in two unrelated families with skin fragility, but cardiac findings highlighted age-dependent penetrance of ARVC. Thus, young, phenotypically normal patients with biallelic JUP mutations should be monitored for development of ARVC.Hassan VahidnezhadLeila YoussefianMasoomeh FaghankhaniNikoo MozafariAmir Hossein SaeidianFatemeh NiaziorimiFahimeh AbdollahimajdSoheila SotoudehFateme RajabiLiaosadat MirsafaeiZahra Alizadeh SaniLu LiuAlyson GuySirous ZeinaliAriana KariminejadReginald T. HoJohn A. McGrathJouni UittoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020) |
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Medicine R Science Q Hassan Vahidnezhad Leila Youssefian Masoomeh Faghankhani Nikoo Mozafari Amir Hossein Saeidian Fatemeh Niaziorimi Fahimeh Abdollahimajd Soheila Sotoudeh Fateme Rajabi Liaosadat Mirsafaei Zahra Alizadeh Sani Lu Liu Alyson Guy Sirous Zeinali Ariana Kariminejad Reginald T. Ho John A. McGrath Jouni Uitto Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility |
| description |
Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC), with skin manifestations, has been associated with mutations in JUP encoding plakoglobin. Genotype–phenotype correlations regarding the penetrance of cardiac involvement, and age of onset have not been well established. We examined a cohort of 362 families with skin fragility to screen for genetic mutations with next-generation sequencing-based methods. In two unrelated families, a previously unreported biallelic mutation, JUP: c.201delC; p.Ser68Alafs*92, was disclosed. The consequences of this mutation were determined by expression profiling both at tissue and ultrastructural levels, and the patients were evaluated by cardiac and cutaneous work-up. Whole-transcriptome sequencing by RNA-Seq revealed JUP as the most down-regulated gene among 21 skin fragility-associated genes. Immunofluorescence showed the lack of plakoglobin in the epidermis. Two probands, 2.5 and 22-year-old, with the same homozygous mutation, allowed us to study the cross-sectional progression of cardiac involvements in relation to age. The older patient had anterior T wave inversions, prolonged terminal activation duration (TAD), and RV enlargement by echocardiogram, and together with JUP mutation met definite ARVC diagnosis. The younger patient had no evidence of cardiac disease, but met possible ARVC diagnosis with one major criterion (the JUP mutation). In conclusion, we identified the same biallelic homozygous JUP mutation in two unrelated families with skin fragility, but cardiac findings highlighted age-dependent penetrance of ARVC. Thus, young, phenotypically normal patients with biallelic JUP mutations should be monitored for development of ARVC. |
| format |
article |
| author |
Hassan Vahidnezhad Leila Youssefian Masoomeh Faghankhani Nikoo Mozafari Amir Hossein Saeidian Fatemeh Niaziorimi Fahimeh Abdollahimajd Soheila Sotoudeh Fateme Rajabi Liaosadat Mirsafaei Zahra Alizadeh Sani Lu Liu Alyson Guy Sirous Zeinali Ariana Kariminejad Reginald T. Ho John A. McGrath Jouni Uitto |
| author_facet |
Hassan Vahidnezhad Leila Youssefian Masoomeh Faghankhani Nikoo Mozafari Amir Hossein Saeidian Fatemeh Niaziorimi Fahimeh Abdollahimajd Soheila Sotoudeh Fateme Rajabi Liaosadat Mirsafaei Zahra Alizadeh Sani Lu Liu Alyson Guy Sirous Zeinali Ariana Kariminejad Reginald T. Ho John A. McGrath Jouni Uitto |
| author_sort |
Hassan Vahidnezhad |
| title |
Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility |
| title_short |
Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility |
| title_full |
Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility |
| title_fullStr |
Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility |
| title_full_unstemmed |
Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility |
| title_sort |
arrhythmogenic right ventricular cardiomyopathy in patients with biallelic jup-associated skin fragility |
| publisher |
Nature Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/ab057a9d7d3946ec9f202a73bd59378c |
| work_keys_str_mv |
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