JUP – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disorder marked by fibrofatty replacement of the right ventricular myocardium and life-threatening ventricular arrhythmias. Plakoglobin, encoded by JUP (HGNC:6207), is a desmosomal armadillo protein essential for cell–cell adhesion in cardiac intercalated discs. Pathogenic variants in JUP disrupt desmosome integrity, leading to mechanical and electrical uncoupling that underpins ARVC pathogenesis (PMID:33831308).

Autosomal recessive JUP mutations were first linked to a cardiocutaneous syndrome featuring arrhythmogenic right ventricular cardiomyopathy with woolly hair and palmoplantar keratoderma (CAPK). A homozygous c.794G>A (p.Arg265His) variant segregated with disease in a consanguineous family presenting alopecia and PPK alongside ARVC (PMID:21668431). Conversely, a dominant‐acting insertion (c.113GCA[3] (p.Ser39dup)) was identified in a German pedigree with ARVC without cutaneous features, showing reduced intercalated disc localization of plakoglobin, desmoplakin, and connexin 43 (PMID:17924338).

De novo JUP mutations further reinforce causality: whole-exome sequencing uncovered c.1729C>T (p.Arg577Cys) in a Chinese ARVC patient without familial history. Bioinformatics predicted deleterious effect, and mutant expression caused overt reduction of DSG2 and connexin 43, disrupting desmosome stability and cardiomyocyte cohesion (PMID:31275992).

Segregation evidence includes at least four affected relatives across distinct pedigrees harboring JUP variants under autosomal dominant and recessive models. Multicenter curation by the ClinGen ARVC Expert Panel classified JUP as definitive for ARVC, confirming its role through robust genetic and experimental concordance (PMID:33831308).

Functional assays demonstrate that dominant and de novo JUP mutations impair plakoglobin incorporation at intercalated discs, diminish key junctional proteins (desmoplakin, DSG2, connexin 43), and alter cell adhesion and signaling pathways. Rescue of adhesion by wild-type plakoglobin in mutant cell lines underscores haploinsufficiency and dominant-negative mechanisms in ARVC.

Collectively, genetic segregation, recurrent and de novo pathogenic variants, and consistent functional deficits establish a definitive association between JUP and ARVC. Plakoglobin mutation screening is clinically indicated for ARVC diagnosis, risk stratification, and familial cascade testing.

Key Take-Home: Pathogenic variants in JUP definitively cause ARVC via disruption of desmosomal integrity, supporting its inclusion as a major diagnostic criterion and target for genetic screening.

References

• The British journal of dermatology • 2011 • Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is caused by a JUP mutation. PMID:21668431
• American journal of human genetics • 2007 • A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. PMID:17924338
• BioMed research international • 2019 • Whole-Exome Sequencing Identified a De Novo Mutation of Junction Plakoglobin (p.R577C) in a Chinese Patient with Arrhythmogenic Right Ventricular Cardiomyopathy. PMID:31275992
• Circulation. Genomic and precision medicine • 2021 • International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework. PMID:33831308

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