JUP (Plakoglobin) — Naxos Disease
Details
JUP encodes plakoglobin (γ-catenin), an armadillo protein and critical component of the cardiac desmosome at the intercalated disc. Homozygous LP/P variants in JUP cause Naxos disease — an autosomal recessive syndrome characterized by the triad of woolly hair, palmoplantar keratoses, and ARVC with near-complete penetrance by adolescence. First described in 1986 on the Greek island of Naxos, the disease is highly prevalent in that region but rare elsewhere. JUP is the only ACM gene in which biallelic pathogenic variants are the predominant disease mechanism.
Key Facts
- Inheritance: Autosomal recessive (homozygous); heterozygous carriers are generally unaffected. (sources/ACM-Genotype-Mx-JCE-2024, rating: high)
- Triad: Woolly hair + palmoplantar keratoses + ARVC. Cardiac phenotype is right-sided with features similar to PKP2-ARVC but significantly more severe clinical course. (sources/ACM-Genotype-Mx-JCE-2024)
- Penetrance: 97% penetrance by adolescence — essentially complete. Biventricular involvement not uncommon. High risk of VAs, precordial T-wave inversions, fibro-fatty replacement including left-sided structural abnormalities. (sources/ACM-Genotype-Mx-JCE-2024)
- Prevalence: High in Naxos, Greece (founder effect); low in other populations. (sources/ACM-Genotype-Mx-JCE-2024)
- Unlike PKP2, where haploinsufficiency is the mechanism, JUP disease requires biallelic loss — making the natural history more predictable and severe. (sources/ACM-Genotype-Mx-JCE-2024)
Contradictions / Open Questions
- Management guidelines are extrapolated from ARVC data — no JUP-specific risk stratification tools exist despite the distinct (more severe) natural history.
- Whether heterozygous JUP carriers have any subclinical phenotype or increased risk is unclear.
- ICD thresholds derived from the ARVC risk calculator may not apply to Naxos disease given its near-complete penetrance and severity.
Connections
- Related to entities/PKP2
- Related to entities/DSP
- Related to entities/DSG2
- Related to entities/DSC2
- Related to entities/ARVC
- Related to concepts/Arrhythmogenic-Cardiomyopathy
- Related to concepts/Desmosome
- Related to sources/ACM-Genotype-Mx-JCE-2024