Desmoplakin and Clinical Manifestations of Desmoplakin Cardiomyopathy

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Desmoplakin and Clinical Manifestations of Desmoplakin Cardiomyopathy

Desmoplakin (DSP), encoded by the DSP gene located on chromosome 6p24.3, is a critical component of desmosomes—specialized structures that maintain cellular adhesion in tissues subjected to mechanical stress, such as the myocardium and epidermis. DSP exists in three isoforms generated through alternative splicing: DSP-I (long), DSP-Ia (intermediate), and DSP-II (short). These isoforms differ primarily in the length of their central alpha-helical rod domains. DSP-I, the predominant cardiac isoform, contains the full-length rod domain, while DSP-Ia retains half and DSP-II lacks two-thirds of this region. Although DSP-II was initially considered skin-specific, low levels of DSP-II transcripts have been detected in cardiac tissues, including the left atrium, ventricle, and interventricular septum. DSP-Ia, found in aortic tissues and epidermal keratinocytes, exhibits minimal expression in the heart.

Structural and Functional Roles of DSP

Desmosomes in cardiomyocytes comprise DSP, desmoglein (DSG), desmocollin (DSC), plakoglobin (PKG), and plakophilin (PKP). DSP anchors intermediate filaments (IFs), such as desmin, to the plasma membrane via its carboxy-terminal plakin repeat domains (PRDs A, B, C) and a glycine-serine-arginine (GSR) domain. This tethering ensures mechanical resilience by distributing forces across cells. DSP also regulates electrical coupling by maintaining connexin 43 (Cx43) gap junctions and voltage-gated sodium channels (Nav1.5). Experimental models show that DSP silencing disrupts Cx43 localization, reduces sodium current density, and slows conduction velocity—key factors in arrhythmogenesis.

DSP is indispensable for embryonic development. Homozygous DSP deletion in mice results in embryonic lethality at embryonic day 6.5 (E6.5) due to cell adhesion defects and impaired proliferation. In Xenopus embryos, DSP facilitates epidermal cell migration during morphogenesis, highlighting its role beyond cardiac tissue.

Molecular Mechanisms Underlying DSP Cardiomyopathy

Wnt/β-Catenin Signaling

DSP mutations disrupt desmosomal integrity, releasing PKG into the nucleus. Nuclear PKG competes with β-catenin for binding to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, suppressing canonical Wnt signaling. This suppression shifts cell fate toward adipogenesis and fibrogenesis instead of myogenesis. For example, the DSP c.832delG frameshift variant upregulates nuclear PKG while downregulating β-catenin, promoting adipose deposition and fibrosis in cardiac tissue.

Hippo/YAP Pathway

DSP deficiency activates the Hippo kinase cascade (MST1/2 and LATS1/2), leading to phosphorylation and inactivation of yes-associated protein (YAP). Inactive YAP fails to promote cardiomyocyte proliferation and inhibits Wnt signaling by sequestering β-catenin in the cytoplasm. This dual dysregulation exacerbates myocardial fibro-adipocytic replacement, a hallmark of arrhythmogenic cardiomyopathy (ACM).

Connexin 43 (Cx43) Dysregulation

DSP stabilizes Cx43 by preventing lysosomal degradation via ERK1/2-MAPK pathway inhibition. Loss of DSP accelerates Cx43 internalization and degradation, impairing intercellular communication. Additionally, DSP interacts with microtubule-binding protein EB1 to guide Cx43 trafficking to the plasma membrane. Mutations in DSP’s N-terminus (e.g., N458Y, I533T) disrupt EB1 binding, leading to aberrant Cx43 localization and gap junction dysfunction.

Inflammatory Response

Myocardial injury in DSP cardiomyopathy triggers a neutrophil-dominated inflammatory infiltrate, with macrophages and T-cells persisting in fibrotic regions. Clinical cases demonstrate elevated 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scans, mimicking myocarditis or sarcoidosis. Recurrent inflammatory episodes may accelerate left ventricular (LV) fibrosis and systolic dysfunction.

Clinical Spectrum of DSP Cardiomyopathy

Left-Dominant Arrhythmogenic Cardiomyopathy

DSP cardiomyopathy, reclassified in 2019 as a distinct ACM subtype, predominantly affects the LV. It is characterized by episodic myocardial injury, fibrosis preceding systolic dysfunction, and high ventricular arrhythmia burden. DSP mutation carriers often present with syncope, sudden cardiac death (SCD), or heart failure. For instance, a DSP c.3735_3741dupAAATCGA variant caused severe LV hypokinesis, dilation, and mid-myocardial delayed enhancement in a patient with exercise-induced SCD. Truncating mutations (e.g., c.6310delA) correlate with aggressive phenotypes, including LV noncompaction (LVNC) and dilated cardiomyopathy (DCM)-like features.

Overlap Syndromes and Misdiagnosis

  1. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC):
    DSP mutations account for 10%–15% of ARVC cases (ARVC8). Unlike PKP2-associated ARVC, DSP cardiomyopathy often involves biventricular or LV-predominant fibrosis, rendering traditional Task Force Criteria less sensitive for diagnosis.

  2. LV Noncompaction (LVNC):
    Truncating DSP mutations (e.g., c.5208_5209delAG) cause trabecular hypertrophy and ventricular noncompaction. A DSP c.1339C>T variant is linked to LVNC with severe early-onset heart failure.

  3. Dilated Cardiomyopathy (DCM):
    Recessive DSP variants (e.g., compound heterozygotes) manifest as early-onset DCM without cutaneous involvement. Progressive fibrosis from recurrent myocardial injury distinguishes DSP cardiomyopathy from idiopathic DCM.

  4. Myocarditis Mimicry:
    Acute LV injury in DSP cardiomyopathy mimics viral myocarditis. A heterozygous DSP p.Arg1458Ter variant was identified in brothers with recurrent exercise-triggered myocarditis. Cardiac MRI shows subepicardial late gadolinium enhancement and inflammation, often misdiagnosed as cardiac sarcoidosis.

Cardio-Cutaneous Syndromes

  1. Naxos Disease and Carvajal Syndrome:
    Recessive DSP mutations cause Naxos disease (woolly hair, palmoplantar keratoderma [PPK], ARVC) and Carvajal syndrome (PPK, woolly hair, LV-dominant cardiomyopathy). Truncations in DSP’s C-terminal plakin domains (e.g., Exons 23–24) disrupt IF binding, leading to early-onset ventricular arrhythmias and heart failure.

  2. Erythro-Keratodermia-Cardiomyopathy (EKC) Syndrome:
    De novo missense mutations in DSP’s spectrin repeat domain (e.g., p.Ser597Leu) cause erythrokeratoderma, ichthyosis, enamel defects, and progressive cardiomyopathy. These mutations impair desmosome assembly and lipid secretion in keratinocytes.

Diagnostic and Therapeutic Implications

Genotype-phenotype correlations reveal that truncating DSP mutations (e.g., c.3737dupA) often cause severe LV dysfunction, while missense variants (e.g., p.His1684Arg) primarily affect ion channels, causing conduction abnormalities. DSP suppression in iPSC-derived cardiomyocytes reduces Nav1.5 and L-type calcium currents, shortens action potential duration, and increases transient outward potassium currents—findings consistent with arrhythmia susceptibility.

Familial screening is critical, as 41% of probands have relatives with SCD. Cardiac MRI and 18F-FDG PET help differentiate DSP cardiomyopathy from inflammatory or ischemic conditions. Emerging therapies targeting Wnt signaling (e.g., lithium) or Hippo-YAP pathways may mitigate fibro-adipogenic remodeling.

Conclusion

DSP cardiomyopathy represents a unique ACM subtype with diverse clinical manifestations, overlapping features with ARVC, LVNC, DCM, and myocarditis. Its pathogenesis involves disrupted cell adhesion, aberrant Wnt/Hippo signaling, and inflammatory cascades. Recognizing genotype-specific patterns—such as LV predominance in truncating mutations or cardio-cutaneous involvement in recessive variants—is essential for accurate diagnosis and risk stratification. Future research must clarify the pathogenicity of DSP polymorphisms and explore targeted therapies to modify disease progression.

doi.org/10.1097/CM9.0000000000001581

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