Desmosome (Cardiac)
Definition
Desmosomes are intercellular junctional complexes at the intercalated disc (ID) of cardiomyocytes that anchor intermediate filaments (desmin) from adjacent cells, providing mechanical resilience under the contractile forces of the beating heart. Their dysfunction is the "final common pathway" of ARVC.
Key Concepts
Structure
- The intercellular face of the desmosome is formed by cadherins desmoglein-2 (DSG2) and desmocollin-2 (DSC2), which bind heterologously across the intercellular space. Calcium ions maintain the hyperadhesive state.
- Intracellularly, the armadillo proteins plakophilin-2 (PKP2) and junction plakoglobin (JUP) connect the cadherin tails to desmoplakin (DSP), which then links to the type III intermediate filament protein desmin (DES).
- PKP2 interacts with DSP at their N-terminal domains; JUP is shared between desmosomes and adherens junctions.
(sources/acm-hrs-2019)
Integration with the Intercalated Disc (Area Composita)
- The cardiac ID is not a set of independent structures but an integrated zone called the area composita — a hybrid of desmosomal and adherens junction proteins that co-exist, creating a mechanically and electrically coupled functional unit.
- Gap junctions (connexin-43/Cx43), adherens junctions (N-cadherin/CDH2), and desmosomes all communicate via shared multifunctional proteins (ZO-1, ankyrin G, β-catenin).
- PKP2 knockdown reduces Cx43 at the ID → decreased conduction velocity → increased re-entry arrhythmias.
- Nav1.5 (SCN5A) co-precipitates with PKP2 and N-cadherin → desmosomal mutations impair sodium current secondarily. (sources/acm-hrs-2019)
Wnt/β-Catenin Signaling and Fibrofatty Replacement
- β-catenin has dual roles: structural (adherens junction-to-actin linker) and signaling (activates Wnt target gene transcription, including Cx43).
- When desmosomal integrity is lost (e.g., PKP2 mutation), β-catenin is released and translocates to the nucleus → activates Wnt signaling → promotes adipogenesis and fibrosis, producing the hallmark fibrofatty replacement of RV myocardium in ARVC. (sources/acm-hrs-2019)
Disease Genes (Desmosomal ACM)
| Gene | Protein | Prevalence | Notable Features |
|---|---|---|---|
| PKP2 | Plakophilin-2 | Most common ARVC | Large deletions 1–2%; truncating variants predominate |
| DSP | Desmoplakin | Common; ARVC + ALVC | Carvajal syndrome (recessive); LGE may precede LV dysfunction |
| DSG2 | Desmoglein-2 | Less common | Rarely recessive |
| DSC2 | Desmocollin-2 | Less common | Rare |
| JUP | Junction plakoglobin | Rare | Naxos disease (recessive; hair/skin abnormalities) |
Non-Desmosomal Genes with Desmosomal Interaction
- TMEM43 (LUMA): Disrupts desmosomal function; p.S358L is a founder variant with male predominance and confirmed ICD survival benefit.
- CDH2 (N-cadherin): Area composita protein; N-cadherin deletion causes dissolution of entire ID structure → ARVC-like phenotype.
- CTNNA3 (αT-catenin): Area composita protein; identified in ARVC patients negative for classical desmosomal gene variants.
(sources/acm-hrs-2019)
Contradictions / Open Questions
- Wnt/β-catenin as fibrofatty driver — other mechanisms present: The β-catenin nuclear translocation / Wnt pathway hypothesis explains fibrofatty replacement in ARVC as the consequence of desmosomal integrity loss. However, the same fibrofatty phenotype appears in non-desmosomal ACM genes (TMEM43, CDH2) — suggesting additional converging pathways exist that the Wnt hypothesis alone does not account for. (sources/acm-hrs-2019)
- Nav1.5 reduction in all ARVC vs. primary desmosomal gene dependence: PKP2 loss reduces Nav1.5 surface expression through disrupted co-localization at the intercalated disc. This mechanism is well-established for PKP2 but may not apply uniformly to other desmosomal genes (DSP, DSG2, DSC2) at the same magnitude. Whether sodium channel dysfunction is a universal feature of all desmosomal ACM or a PKP2-specific phenomenon with implications for conduction and arrhythmia is incompletely resolved. (sources/acm-hrs-2019)
Connections
- Related to concepts/Arrhythmogenic-Cardiomyopathy
- Related to concepts/Final-Common-Pathway
- Related to entities/ARVC
- Related to entities/PKP2
- Related to entities/DSP
- Related to entities/SCN5A