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 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.

Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

“…These carriers developed severe and sometimes lethal skin fragility, in combination with PPK and alopecia in homozygous c.201del carriers. Cardiomyopathy was not observed in any but one patient with old age [66]. Meanwhile, no other patients with PG reduction (≤50% protein) have been reported.…”

“…This suggests that threshold levels for cardiomyopathy in mice span between 10-40% of native protein. Two human variants (c.201del and c.1615C > T, nonsense) were reported to induce complete PG depletion in homozygous patients [66,68]. These carriers developed severe and sometimes lethal skin fragility, in combination with PPK and alopecia in homozygous c.201del carriers.…”

Isolated JUP plakoglobin gene mutation with left ventricular fibrosis in familial arrhythmogenic right ventricular cardiomyopathy

“…Its prevalence in the general population is estimated at 1 in 5000, but closer to 1 in 2000 in select European countries and constitutes up to 20% of sudden cardiac death cases in individuals under 30 years of age. 5,6 In addition, phenotypic expression in males differs, in which males have a more malignant disease course and develop lifethreatening ventricular arrhythmias at an earlier age, possibly due to differences in sex hormones (testosterone) and increased level of physical activity, which may contribute to a greater degree of mechanical cardiac stress. 7 Due to an expanding phenotypic spectrum of ACM, from multigene variability in expression as well as incomplete penetrance, the diagnosis has been challenging requiring revisions to originally published criteria.…”

“…It is characterized by fibro‐fatty tissue substitution of healthy ventricular myocardium, predisposing these patients to ventricular tachycardia, heart failure, and sudden cardiac death. Its prevalence in the general population is estimated at 1 in 5000, but closer to 1 in 2000 in select European countries and constitutes up to 20% of sudden cardiac death cases in individuals under 30 years of age 5,6 . In addition, phenotypic expression in males differs, in which males have a more malignant disease course and develop life‐threatening ventricular arrhythmias at an earlier age, possibly due to differences in sex hormones (testosterone) and increased level of physical activity, which may contribute to a greater degree of mechanical cardiac stress 7 …”

Cheek-Pro-Heart: What Can the Buccal Mucosa Do for Arrhythmogenic Cardiomyopathy?

“…As mentioned above, desmosomes are particularly prominent in those tissues, which are exposed to mechanical forces, such as the skin and the heart [ 16 ]. The junctional signal for PG was shown to be depressed in skin samples from children with severe ACM manifestation, but patients are not routinely subjected to skin biopsy sampling unless they also show cutaneous abnormalities [ 56 , 57 ]. The buccal epithelium, however, is a tissue, which can be accessed very easily and can be sampled in a minimally invasive and risk-free manner [ 58 ].…”