DSP

Desmoplakin (DSP) is the central structural component of the desmosomal plaque that anchors intermediate filaments and maintains tissue integrity in skin and myocardium (PMID:20302578, PMID:25659760). Its C-terminal plakin repeat domain and rod domain are essential for forming the inner dense plaque and inserting tonofilaments; homozygous truncation removing the rod and C-terminus abolishes inner dense plaque formation and intermediate filament anchorage, while truncation of the plakin repeat domain recapitulates combined cardiac and cutaneous disease (PMID:20302578, PMID:25659760). The protein is expressed as two isoforms, and the longer desmoplakin-I transcript is the major cardiac isoform, explaining why isoform-specific truncations dictate cardiac involvement and why variants causing nonsense-mediated decay of both isoforms confer greater arrhythmic risk than haploinsufficiency of one (PMID:19016709, PMID:36580316). Beyond structural anchorage, DSP variants disrupt junctional organization more broadly: missense mutations clustered in spectrin repeat 6 cause aberrant localization of desmosomal proteins and connexin-43, desmosome aggregation, and lipid secretory defects in skin (PMID:26604139), and reduced DSP expression mislocalizes connexin-43 and, under hemodynamic and catecholaminergic stress, drives heart failure and ventricular arrhythmias (PMID:36231013). DSP variants also directly alter cardiomyocyte electrophysiology, reducing Nav1.5 sodium and L-type calcium currents and increasing transient-outward potassium current to shorten action potential duration (PMID:32706220). DSP transcription is controlled by mechanical cues: stiff matrix demethylates a proximal promoter region permitting EGR1 binding to drive DSP overexpression, a process reversible by targeted promoter methylation (PMID:29924937). Collectively, these mechanisms produce arrhythmogenic cardiomyopathy, skin fragility, and cardio-cutaneous syndromes (PMID:19016709, PMID:26604139, PMID:25659760).

1. 1991 Medium

   Establishing the chromosomal location of DSP provided the genomic anchor needed to link the gene to inherited disease loci.

   Evidence PCR-based chromosomal assignment using human-rodent somatic cell hybrid panels

   PMID:1889810

   Open questions at the time

   • No functional or mechanistic information about the protein
   • No isoform structure defined at this stage
2. 2008 Medium

   Isoform-specific frameshift mutations resolved why DSP defects produce cardiac involvement while related desmosomal gene defects do not, linking the cardiac phenotype to the desmoplakin-I isoform expressed in heart.

   Evidence Human DSP mutation analysis with isoform-level genotype-phenotype correlation in ectodermal dysplasia-skin fragility patients

   PMID:19016709

   Open questions at the time

   • Mechanism connecting isoform loss to specific cardiac structural defect not shown at molecular level
   • Single study
3. 2010 Medium

   A homozygous truncating deletion established that the rod domain and C-terminus are required for inner dense plaque assembly and intermediate filament anchorage in vivo.

   Evidence DSP mutation analysis with electron microscopy of patient skin biopsies

   PMID:20302578

   Open questions at the time

   • Does not isolate rod versus C-terminal contributions
   • Skin readout only; cardiac ultrastructure not examined
4. 2015 Medium

   Mapping de novo missense mutations to spectrin repeat 6 identified a specific functional region whose disruption mislocalizes desmosomal proteins and connexin-43 and impairs lipid secretion.

   Evidence Human genetics with immunofluorescence and electron microscopy in patient skin (EKC syndrome)

   PMID:26604139

   Open questions at the time

   • Molecular interaction partner of SR6 not defined
   • Cardiac mechanism of SR6 variants not directly assayed
5. 2015 Medium

   A C-terminal plakin repeat domain truncation in mouse demonstrated in a controlled genetic background that this domain is required for both cardiac and cutaneous desmosomal function.

   Evidence Spontaneous mouse Dsp frameshift mutant with histopathology and ECG analysis

   PMID:25659760

   Open questions at the time

   • Does not dissect cell-autonomous mechanism
   • Molecular consequence for filament binding not directly measured
6. 2015 Low

   Immunophenotyping of an SR6-mutation patient described a Th1/Th17/IL-23 inflammatory signature accompanying DSP skin disease.

   Evidence Blood and skin immunophenotyping with targeted ustekinumab therapy in a single patient

   PMID:29066275

   Open questions at the time

   • Single patient; no direct molecular link between DSP and immune signaling established
   • Causality between DSP loss and cytokine skewing unproven
7. 2018 High

   Identifying matrix stiffness-driven, EGR1-dependent promoter demethylation defined a mechanotransduction mechanism controlling DSP expression beyond its structural role.

   Evidence Polyacrylamide stiffness system with ChIP, EMSA, and CRISPR/dCas9-Dnmt3A epigenome editing in lung epithelial cells

   PMID:29924937

   Open questions at the time

   • Mechanism by which stiffness triggers demethylation upstream of EGR1 not defined
   • Relevance to cardiac DSP regulation not tested
8. 2020 Medium

   Patient iPSC-cardiomyocytes showed that a DSP missense variant directly alters ion channel currents, expanding DSP pathology from structural failure to electrical dysfunction.

   Evidence iPSC-derived cardiomyocytes with whole-cell voltage- and current-clamp electrophysiology (H1684R variant)

   PMID:32706220

   Open questions at the time

   • Mechanism linking DSP to channel function not resolved
   • Single variant in single patient line
9. 2022 Medium

   A humanized knock-in mouse demonstrated that reduced DSP causes connexin-43 mislocalization at baseline and stress-triggered arrhythmias and heart failure, connecting variant burden to a physiological disease trajectory.

   Evidence Dsp R451G knock-in mice with pressure overload, catecholaminergic challenge, connexin-43 immunofluorescence, and cardiac functional measurements

   PMID:36231013

   Open questions at the time

   • Molecular basis of connexin-43 mislocalization not defined
   • Single variant model
10. 2022 Medium

    A multicenter cohort established that truncating variant location, specifically loss of both isoforms via nonsense-mediated decay, independently predicts ventricular arrhythmia risk.

    Evidence Multicenter cohort with variant-location and survival analysis against ClinVar/gnomAD controls

    PMID:36580316

    Open questions at the time

    • Does not establish molecular threshold of DSP dosage for arrhythmia
    • Mechanistic link between dosage and electrical instability inferred, not measured

• The molecular mechanism by which desmoplakin variants alter ion channel currents and connexin-43 localization remains unresolved.
• No direct physical link between DSP and Nav1.5, L-type calcium channels, or connexin-43 trafficking established
• Domain-resolved structural model of DSP-intermediate filament anchorage not defined in the corpus