ArticleJCI insight2023
Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 25 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
- Consensus Recommendations for Management of Darier Disease: A Practical Approach.Dermatology and therapy · 2026Article
- Transforming destructive mechanical cues into therapeutic power: Activation of PIEZO1 and TRPV4 counteracts mechano-induced damage of cellular junctions in Hailey-Hailey disease.Journal of advanced research · 2026Article
- Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.Science advances · 2026Article
- Unexpected remission of Darier disease in a melanoma patient treated with trametinib and naporafenib.JAAD case reports · 2026Article
- Cadherin regulation of endoplasmic reticulum-plasma membrane contact sites.Cell reports · 2026Article
- Flower dependent trafficking of lamellar bodies facilitates maturation of the epidermal barrier.Nature communications · 2025Article
- Review
- Darier disease: Current insights and challenges in pathogenesis and management.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
- Calcium dynamics of skin-resident macrophages during homeostasis and tissue injury.Molecular biology of the cell · 2024Article
- Diversity of human skin three-dimensional organotypic cultures.Current opinion in genetics & development · 2024Review
- ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.JCI insight · 2024Article
- Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.EMBO molecular medicine · 2024Article
- NovelBiomedicines · 2024Article
- Keratin isoform shifts modulate motility signals during wound healing.bioRxiv : the preprint server for biology · 2024Article
- Th17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets.Nature communications · 2023Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than 2 decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2-knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed RNA sequencing and proteomics analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAPK signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings, with lesions showing keratin deficiency, cadherin mislocalization, and ERK hyperphosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multiomic analysis with human organotypic epidermis as a preclinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified MEK inhibition as a treatment strategy for Darier disease.
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What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.