JUP – Naxos disease

Naxos disease was first recognised in 1984 on a remote Greek island by clinicians observing a distinct combination of ventricular tachycardia, woolly hair, and palmoplantar keratoderma. This triad pointed to a cardiocutaneous syndrome with autosomal recessive inheritance. Pedigree analysis in four families with nine affected individuals mapped the locus to chromosome 17q21 and identified homozygous JUP mutations as causative (PMID:40246227). The initial publication in 1986 formally defined Naxos disease, linking desmosomal dysfunction to arrhythmogenic right ventricular cardiomyopathy (ARVC). Subsequent international collaborations and the NAXCARE registry have refined disease natural history. The unique cutaneous and hair phenotypes enable early detection of at‐risk relatives.

Naxos disease is inherited in an autosomal recessive pattern through biallelic loss‐of‐function variants in JUP. At least nine probands from four unrelated pedigrees harbour homozygous or compound heterozygous JUP variants (PMID:40246227). The variant spectrum is dominated by C‐terminal frameshift and truncating alleles, including c.1807del (p.Val603fs). To date, no recurrent founder mutations beyond the original cohort have been reported in diverse populations. Penetrance is complete in homozygotes with consistent cardiac and cutaneous manifestations. Carrier frequency estimates remain undefined due to rarity.

Functional assays in recombinant cell models demonstrate that JUP truncating mutations abolish plakoglobin incorporation into desmosomes and reduce cell‐cell adhesion strength. HEK293 cells expressing the C‐terminal mutation exhibit markedly decreased intercellular adhesion and increased migration velocity, reflective of compromised mechanical coupling (PMID:18937352). Patient myocardial tissue exhibits markedly diminished plakoglobin staining at intercalated discs. These experiments confirm that JUP deficiency disrupts both structural desmosomal integrity and electrical coupling. The concordance between cellular phenotypes and patient manifestations underscores a loss‐of‐function mechanism. No in vivo animal models have yet recapitulated the full cardiocutaneous phenotype.

Pathogenic JUP variants result in haploinsufficiency of plakoglobin, a critical component of cardiac and epidermal desmosomes. Loss of plakoglobin impairs desmosomal cell‐cell adhesion, leading to myocyte detachment, fibro‐fatty replacement, and ventricular arrhythmias. In the epidermis, defective desmosomes manifest as woolly hair due to hair shaft fragility and palmoplantar keratoderma through skin barrier disruption. This dual tissue vulnerability illustrates the interdependence of desmosomal integrity in mechanical resilience. The identification of JUP as the gene underlying Naxos disease shifted paradigms in ARVC research toward cell adhesion defects. Restoration of plakoglobin function in patient‐derived cardiomyocytes remains an emerging therapeutic strategy.

Clinically, Naxos disease is characterised by early onset ventricular arrhythmias that may progress to sudden cardiac death by early adulthood. The presence of woolly hair and palmoplantar keratoderma in infancy provides early diagnostic markers. Genetic testing for JUP variants enables presymptomatic identification and family cascade screening. Management includes standard ARVC interventions, such as beta‐blockers, implantable cardioverter‐defibrillators, and lifestyle modifications. The distinct phenotypic presentation facilitates targeted commercial diagnostic panels. Longitudinal registry data continue to inform risk stratification and therapeutic outcomes.

In summary, biallelic truncating variants in JUP are definitively established as the cause of Naxos disease. The combination of robust genetic segregation in four families and concordant functional data yields a Definitive ClinGen gene‐disease classification. This evidence supports clinical genetic testing, early intervention, and family counselling. Additional studies into genotype–phenotype correlations and potential gene therapy approaches are warranted. The JUP–Naxos disease link exemplifies the importance of desmosomal integrity for cardiocutaneous health. Key Take-home: Genetic confirmation of JUP mutations in Naxos disease enables accurate diagnosis, risk assessment, and personalized management.

References

• Hellenic journal of cardiology • 2025 • The History of Naxos Disease: Pioneering Innovation and Collaboration with Limited Means. PMID:40246227
• Cell motility and the cytoskeleton • 2008 • Disparate effects of different mutations in plakoglobin on cell mechanical behavior. PMID:18937352

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