ArticleThe Journal of investigative dermatology2014
SERCA2 dysfunction in Darier disease causes endoplasmic reticulum stress and impaired cell-to-cell adhesion strength: rescue by Miglustat.
Article in The Journal of investigative dermatology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 86 citations in OpenAlex.
- Darier disease-A review highlighting new insights from the Darier Disease International Task Force.Journal of the European Academy of Dermatology and Venereology : JEADV · 2026Review
- Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.Science advances · 2026Article
- Cadherin regulation of endoplasmic reticulum-plasma membrane contact sites.Cell reports · 2026Article
- Mimicking Darier Disease In Vitro: A Human Epidermal Organoid Approach.Experimental dermatology · 2025Article
- PERK protein kinase facilitates keratinocyte collective cell migration by engagement with cell adhesion molecules, independent of its kinase activity.Molecular biology of the cell · 2025Article
- Pemphigus Vulgaris Autoantibodies Induce an Endoplasmic Reticulum Stress Response.The Journal of investigative dermatology · 2025Article
- Topographical variations in the skin barrier and their role in disease pathogenesis.Journal of the European Academy of Dermatology and Venereology : JEADV · 2025Review
- Pumping the Breaks on Acantholytic Skin Disorders: Targeting Calcium Pumps, Desmosomes, and Downstream Signaling in Darier, Hailey-Hailey, and Grover Disease.The Journal of investigative dermatology · 2025Review
- Patients with Darier disease have an increased risk of keratinocyte carcinoma: a Swedish registry-based nationwide cohort study.Orphanet journal of rare diseases · 2024Article
- Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.EMBO molecular medicine · 2024Article
- Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.Acta dermato-venereologica · 2024Article
- Dermoscopy as a Noninvasive Diagnostic Tool for Hailey-Hailey Disease and Darier Disease.Dermatology and therapy · 2023Article
- Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease.JCI insight · 2023Article
- Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis.JCI insight · 2023Article
- Architecture and dynamics of a desmosome-endoplasmic reticulum complex.Nature cell biology · 2023Article
- Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation.Journal of lipid research · 2023Article
- Regional Differences in the Permeability Barrier of the Skin-Implications in Acantholytic Skin Diseases.International journal of molecular sciences · 2021Article
- Darier Disease - A Multi-organ Condition?Acta dermato-venereologica · 2021Review
- Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis.Cancers · 2020Review
- IFI6 depletion inhibits esophageal squamous cell carcinoma progression through reactive oxygen species accumulation via mitochondrial dysfunction and endoplasmic reticulum stress.Journal of experimental & clinical cancer research : CR · 2020Article
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5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Darier disease (DD) is a severe dominant genetic skin disorder characterized by the loss of cell-to-cell adhesion and abnormal keratinization. The defective gene, ATP2A2, encodes sarco/endoplasmic reticulum (ER) Ca2+ -ATPase isoform 2 (SERCA2), a Ca2+ -ATPase pump of the ER. Here we show that Darier keratinocytes (DKs) display biochemical and morphological hallmarks of constitutive ER stress with increased sensitivity to ER stressors. Desmosome and adherens junctions (AJs) displayed features of immature adhesion complexes: expression of desmosomal cadherins (desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3)) and desmoplakin was impaired at the plasma membrane, as well as E-cadherin, β-, α-, and p120-catenin staining. Dsg3, Dsc3, and E-cadherin showed perinuclear staining and co-immunostaining with ER markers, indicative of ER retention. Consistent with these abnormalities, intercellular adhesion strength was reduced as shown by a dispase mechanical dissociation assay. Exposure of normal keratinocytes to the SERCA2 inhibitor thapsigargin recapitulated these abnormalities, supporting the role of loss of SERCA2 function in impaired desmosome and AJ formation. Remarkably, treatment of DKs with the orphan drug Miglustat, a pharmacological chaperone, restored mature AJ and desmosome formation, and improved adhesion strength. These results point to an important contribution of ER stress in DD pathogenesis and provide the basis for future clinical evaluation of Miglustat in Darier patients.
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