Desmosomes in the Heart: A Review of Clinical and Mechanistic Analyses

Figures & data

Figure 1. Intercellular junctions in epithelial and cardiac tissues. (A) In epithelial tissues, adherens junctions and desmosomes comprise discrete plaques that respectively tether actin and intermediate filaments to sites of cell–cell contact (Harmon & Green, 2013; Simpson et al., 2011). (B) In cardiac tissue, components of desmosomes and adherens junctions intermingle as a hybrid area composita that stabilizes adjacent gap junctions (Bolling & Jonkman, 2009; Franke et al., 2006). Desmoplakin may localize to N-cadherin via plakoglobin (Cowin et al., 1986), while αT-catenin could associate with desmosomal cadherins through plakophilin 2 (Goossens et al., 2007). Both desmocollin 2 and plakophilin 2 have been shown to associate with connexin43 (Gehmlich et al., 2011a; Li et al., 2009; Oxford et al., 2007), potentially forming direct links between the area composita and gap junction plaques.

Table 1. Cardiomyopathy (CM) classifications. Generalized clinical findings and etiology of each condition, in addition to those of unclassified cardiomyopathies (left ventricular noncompaction, stress-induced, cirrhotic, etc.) are further described in referenced reviews (Elliott, 2008; Harvey & Leinwand, 2011; Maron et al., 2006).

Classification	Tissue characteristics	Common etiologies
Arrhythmogenic CM	Fibro-fatty replacement of ventricular muscle, sparing interventricular septum.	Mutations in desmosomal proteins. Non-familial forms may be linked to inflammation.
Dilated CM	Dilatation and impaired contraction of ventricles, most significantly in the left ventricle.	Idiopathic or secondary to systemic disorders (i.e. infection or systemic toxins). Familial forms due to mutations in cytoskeletal, sarcomeric, nuclear, or junctional proteins.
Hypertrophic CM	Ventricular hypertrophy (involves interventricular septum) with disorganization of cardiac myocytes.	Mutations in sarcomeric proteins; also linked to metabolic disorders.
Restrictive CM	Increased stiffness of myocardium (without alterations in myocyte arrangement), causing elevated ventricular pressures.	Idiopathic or secondary to systemic disorders/injury to cardiac tissue. Familial forms due to mutations in sarcomeric proteins.

Table 2. Mutations associated with AC and AC-overlap syndromes. Detailed descriptions of the listed mutations can be found in the literature cited in this text and elsewhere (Rickelt & Pieperhoff, 2012; van der Zwaag et al., 2009).

Gene target	Protein function
DSG2	Desmoglein 2 (Dsg2): desmosomal cadherin with extracellular domains linking desmosomes of neighboring cells
DSC2	Desmocollin 2 (Dsc2): desmosomal cadherin with extracellular domains linking desmosomes of neighboring cells
PG	Plakoglobin (Pg): desmosomal armadillo protein that links DP to desmosomal cadherins. Has dual localization to classical cadherins of adherens junctions
PKP2	Plakophilin 2 (PKP2): desmosomal armadillo protein that links DP to desmosomal cadherins
DSP	Desmoplakin (DP): desmosomal plakin family protein known for tethering intermediate filaments to desmosomal plaques
TGFB3	Transforming growth factor β3 (TGF-β3): secreted factor involved in extracellular matrix deposition and cell signaling
CTNNA3	alphaT-catenin (αT-catenin): adherens junction component linking actin to sites of cell-cell contact
PLN	Phospholamban (PLN/PLB): membrane protein of the sarcoplasmic reticulum that regulates the SERCA2a calcium ATPase
TMEM43	Transmembrane protein 43/LUMA: protein of inner nuclear membrane that binds lamins and emerin
LMNA	Lamin A/C: proteins of inner nuclear membrane involved in nuclear stability and chromatin structure
TTN	Titin/connectin: sarcomeric protein that serves as a molecular spring between sarcomeric Z and M lines
DES	Desmin: intermediate filament protein expressed in muscle cells

Figure 2. Theories of AC pathogenesis. AC may arise from cardiac myocyte degeneration, inflammation of myocardium from infection by cardiotropic pathogens, and/or transdifferentiation of cardiac myocytes or progenitor cells into fat- and fibrotic scar-producing cells (Basso et al., 2011; Herren et al., 2009).

Table 3. Potential mechanisms of AC mutation pathogenicity. Select findings from mouse models and/or in vitro studies are highlighted here, with further information available in the text.

Mechanism	Targeted Protein	Summary of Findings	Citation
Cell death	Dsg2	Transgenic expression of N271S (equivalent of human Dsg2 N266S) increases cell necrosis	Pilichou et al. (2009)
	Dsg2	Mice lacking Dsg2 ectodomain exhibit increased cardiac myocyte death and fibrosis	Krusche et al. (2011)
	DP	Transgenic expression of DP R2834H increases cell apoptosis	Yang et al. (2006)
Transcriptional activity	Dsg2	Mice lacking Dsg2 ectodomain have increased mRNA expression of c-Myc, ANF, BNF, CTGF, GDF15	Krusche et al. (2011)
	Pg	Cardiac-restricted deletion of Pg leads to increase of β-catenin signaling in nucleus	Li et al. (2011b)
	Pg	Cardiac-restricted deletion of Pg leads to increase in TGF-β-mediated signaling	Li et al. (2011a)
	DP/Pg	Cardiac-restricted deletion of DP leads to nuclear translocation of Pg with expression of pro-adipogenic and pro-fibrotic genes	Garcia-Gras et al. (2006)
	Pg	Transgenic expression of truncated Pg increases expression of adipogenic factors	Lombardi et al. (2011)
	PKP2	iPSC-derived cardiac myocytes expressing PKP2 c.2484C> T demonstrate nuclear translocation of Pg with decreased β-catenin transcriptional activity	Kim et al. (2013)
Gap junction or ion channel abnormalities	Dsg2	Transgenic expression of N271S (equivalent of human Dsg2 N266S) compromises ventricular activation time	Rizzo et al. (2012)
	Dsc2	Q851fsX855 compromises association of Dsc2a with Cx43 and Pg	Gehmlich et al. (2011a)
	PKP2	Mouse models of PKP2 haploinsufficiency exhibit sodium current deficiencies	Cerrone et al. (2012)
Protein stability and/or modification	Dsg2	C813R targeting ICS alters Dsg2 protein migration on gel electrophoresis	Gehmlich et al. (2010)
	Dsg2	V977fsX1006 targeting DUR increases rate of Dsg2 endocytosis	Chen et al. (2012)
	Dsg2	R46Q targeting proprotein convertase cleavage site impairs Dsg2 prodomain cleavage	Gaertner et al. (2012)
	Dsc2	R203C and T275M impair Dsc2 prodomain cleavage	Gehmlich et al. (2011b)
	Dsc2	E102K and I345T increase Dsc2 cytoplasmic localization	Beffagna et al. (2007)
	Pg	S39_K40insS increases ubiquitylation and cytoplasmic localization of Pg	Asimaki et al. (2007)
	PKP2	c.2386T> C increases degradation of PKP2 by calpain proteases	Kirchner et al. (2012)
	DP	R1269X and K324_E325del lead to degradation of DP, producing functional haploinsufficiency	Rasmussen et al. (2013a)

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