Experimental Dermatology最新文献

{"title":"Multimodal Second-Harmonic-Generation, Two-Photon Excitation Fluorescence, and Brillouin Microscopy for Visualising Dermal Mechanical Properties in Ex Vivo Human Skin","authors":"Eiji Hase, Naoya Okubo, Yuki Ogura, Takeo Minamikawa, Takeshi Yasui","doi":"10.1111/exd.70081","DOIUrl":"https://doi.org/10.1111/exd.70081","url":null,"abstract":"<p>Multiphoton microscopy, particularly second-harmonic-generation (SHG) and two-photon excitation fluorescence (TPEF) microscopy, has been a powerful tool for observing the structural and compositional remodelling of the dermal extracellular matrix (ECM) as it selectively visualises collagen and elastic fibres [<span>1</span>]. Therefore, combining data from multiphoton microscopy with mechanical tests offers valuable insights into how ECM remodelling resulting from disease or ageing affects the mechanical properties of the dermis. Although various mechanical tests such as rheology [<span>2</span>], atomic force microscopy-based microindentation [<span>3</span>], and ultrasound [<span>4</span>] are commonly used to assess mechanical properties, their spatial resolution or field of view often do not align with that of multiphoton microscopy, limiting the integration of findings related to ECM remodelling and mechanics.</p><p>In this study, we used Brillouin microscopy [<span>5</span>], which provides information about the viscoelastic properties of biological tissues with sub-micrometre, three-dimensional spatial resolution in a label-free, non-contact manner, and combined it with multiphoton microscopy as an alternative to traditional mechanical tests.</p><p>We integrated multiphoton microscopy and Brillouin microscopy into a single microscope, allowing switching between them (Figure S1). A femtosecond optical parametric oscillator (central wavelength = 800 nm, pulse duration ≈ 110 fs, repetition rate = 80 MHz) and the laser scanning system were used to capture SHG and TPEF images, visualising the distribution of collagen and elastic fibres, respectively. For Brillouin microscopy, a single-mode diode-pumped solid-state laser (wavelength = 532 nm) was used, and the Brillouin spectra were measured by a tandem VIPA spectrometer and an EMCCD camera (exposure time = 100 ms). A normal abdominal skin sample from a healthy Caucasian female, provided by Obio LLC (CA, USA), was embedded in optimal cutting temperature (OCT) compound, flash-frozen, and stored at −80°C. An 8 μm-thick section was then analysed using multimodal microscopy. To mimic physiological conditions, the sample was kept moist by applying phosphate-buffered saline (PBS) solution.</p><p>Figure 1a shows a bright-field image of the sample, with the red square indicating the dermal area measured by multimodal microscopy. The multiphoton imaging results, shown in Figure 1b,c, visualised that both collagen and elastin exist on fibres, with collagen being more densely distributed compared to the sparser distribution of elastin. The optical frequency shift of Brillouin scattering, namely Brillouin shift, is proportional to the longitudinal modulus, which is defined as the ratio of uniaxial stress to strain under a longitudinally confined condition [<span>5</span>]. Therefore, the Brillouin image shown in Figure 1d reflects the distribution of the local mechanical property linked to elasticity. F","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Experience of Risankizumab in Patients With a History of Erythrodermic Psoriasis","authors":"Che-Chia Hsu,&nbsp;Chang-Yu Hsieh,&nbsp;Tsen-Fang Tsai","doi":"10.1111/exd.70080","DOIUrl":"https://doi.org/10.1111/exd.70080","url":null,"abstract":"<div>\u0000 \u0000 <p>Erythrodermic psoriasis (EP) is a severe and challenging variant of psoriasis that often shows poor drug survival. While risankizumab, an IL-23 inhibitor, has demonstrated efficacy in patients with moderate-to-severe plaque psoriasis, its effectiveness in patients with a history of EP is less explored. This study aimed to evaluate treatment response to risankizumab and identify potential predictors influencing the treatment response. In this single-center, longitudinal retrospective study, we included 56 patients treated with risankizumab between August 1, 2016, and June 1, 2023, of whom 22 had a history of EP. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI), and the impact of patient characteristics, including prior biologic exposure and HLA-Cw genotypes, on treatment response was analysed using the Mann–Whitney <i>U</i> test. Throughout the 100-week follow-up, patients with a history of EP exhibited a poorer treatment response compared to those without such a history. Among patients with a history of EP, those with prior exposure to guselkumab and those treated with more than five biologics demonstrated a decreased response to risankizumab. Additionally, there was a non-significant trend indicating that HLA-Cw1–negative patients responded better to risankizumab. This case series indicated that risankizumab might be an effective and sustainable treatment option for most patients with a history of EP. However, prior exposure to multiple biologics, particularly those with a similar mode of action targeting IL-23, may reduce its effectiveness. The potential association between HLA-Cw1 genotype and treatment response warrants further investigation.</p>\u0000 </div>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skin-Protective Performance of Alternative Stratum Corneum Formed by a Pseudo-Ceramide-Containing Steroid Lamellar Cream","authors":"Masafumi Yokota,&nbsp;Tomohiro Matsumoto,&nbsp;Akane Kawamoto,&nbsp;Kumiko Dojo,&nbsp;Sumika Toyama,&nbsp;Catharina Sagita Moniaga,&nbsp;Junko Ishikawa,&nbsp;Daiki Murase,&nbsp;Noriyasu Ota,&nbsp;Mitsutoshi Tominaga,&nbsp;Kenji Takamori","doi":"10.1111/exd.70041","DOIUrl":"https://doi.org/10.1111/exd.70041","url":null,"abstract":"<p>Ceramides in the stratum corneum (SC) are important for epidermal barrier function. We previously developed a synthetic pseudo-ceramide for medical (SPCM)-containing steroid cream [SPCM (+)]. This cream forms films on the skin surface and exerts anti-inflammatory effects through steroids. However, the preventive effects of this cream on the disruption of the skin barrier remained unclear. Therefore, in this study, we aimed to evaluate the protective role of SPCM (+) cream against atopic dermatitis (AD)-associated protease allergens on the skin in recovery from barrier-broken skin. We used three-dimensional (3D) skin and mouse models of disrupted skin barriers to evaluate the protective effect of SPCM (+) cream against V8 protease produced by <i>Staphylococcus aureus</i>. In NC/Nga mice with itching caused by living mites, SPCM (+) cream was repeatedly applied once a day for 2 weeks, and scratching behaviour was assessed every week using the MicroAct system. In the 3D skin model, the SPCM (+) cream directly blocked SC degradation by V8 protease of <i>S. aureus</i> and suppressed the expression of interleukin-36 gamma. The application of SPCM (+) cream to mite-parasitised mice suppressed scratching, reduced elevated activity of skin proteases, and inhibited upregulation of thymic stromal lymphopoietin. These beneficial effects of SPCM (+) cream were not observed with steroid creams without SPCM. These results suggest that the SPCM (+) cream is effective in relieving inflammation and itching by protecting the skin from proteases and allergens through its lamellar structure. This cream may be a promising treatment option for skin barrier disorders including AD and xerosis.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IKZF1 and Ikaros Overexpression Results in Alopecia Areata-Like Phenotype in Mice","authors":"Yukiyasu Arakawa,&nbsp;Risa Tamagawa-Mineoka,&nbsp;Mayumi Ueta,&nbsp;Mari Nakanishi,&nbsp;Hiromi Nishigaki,&nbsp;Norito Katoh","doi":"10.1111/exd.70074","DOIUrl":"https://doi.org/10.1111/exd.70074","url":null,"abstract":"<div>\u0000 \u0000 <p>Ikaros, which is encoded by the Ikaros family zinc finger 1 (<i>IKZF1</i>) gene, is a zinc finger transcription factor. We have previously generated K5-<i>Ikzf1</i>-EGFP transgenic mice (<i>Ikzf1</i> Tg) by introducing the IKZF1 isoform into epithelial cells expressing keratin 5, which develop patchy alopecia. However, there has been no detailed in vivo investigation of the function of <i>IKZF1</i> in alopecia or of Ikaros expression in hair follicles of alopecia patients. Our aim was to investigate whether <i>IKZF1</i> overexpression is involved in the pathogenesis of alopecia areata (AA) using <i>Ikzf1</i> Tg and to examine Ikaros expression in human scalp skin. We grossly and histologically examined the alopecic lesions of <i>Ikzf1</i> Tg and the skin of wild-type (WT) mice and the associated mRNA expression of inflammatory mediators. We also examined Ikaros' expression in human scalp skin. Grossly and histologically, we found that the <i>Ikzf1</i> Tg developed AA-like lesions. Immunohistochemically, the hair follicles of the <i>Ikzf1</i> Tg expressed high levels of the NKG2D ligand H60 and contained infiltrating CD8⁺NKG2D⁺ T cells. Interleukin 15, tumour necrosis factor-α, CXC chemokine ligand (Cxcl)1, Cxcl10, Cxcl11, signal transducer and activator of transcription (STAT)1, STAT3, Janus kinase (JAK)1 and JAK3 mRNA expression were significantly higher in the alopecic lesions of the <i>Ikzf1</i> Tg than in the WT mice. <i>Ikzf1</i> Tg given corticosteroid injections exhibited hair regrowth. Immunohistochemical analysis of scalp hair follicles showed that Ikaros was more highly expressed in AA patients than in non-AA controls. Our study suggests that <i>IKZF1</i> and Ikaros are involved in the pathogenesis of AA.</p>\u0000 </div>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Ammonium Carboxylate Salt of Undecylenic Acid for the Topical Treatment of Gram-Positive and Antibiotic-Resistant Skin Infections","authors":"Alyce Mayfosh,&nbsp;Thomas Rau","doi":"10.1111/exd.70075","DOIUrl":"https://doi.org/10.1111/exd.70075","url":null,"abstract":"<p>Uncomplicated topical skin infections like impetigo, caused by gram-positive bacteria such as <i>Staphylococcus aureus</i> and <i>Streptococcus pyogenes</i>, are a common global health issue, particularly affecting children. With increasing antimicrobial resistance, conventional treatments such as mupirocin are becoming ineffective, highlighting the necessity for new antimicrobial development. Fatty acids have long shown potential as novel antimicrobials, but their development has been limited by solubility and efficacy concerns in topical applications. We previously discovered that combining the amino acid L-arginine with an 11-carbon fatty acid, undecylenic acid, produced a water-soluble ammonium carboxylate salt, arginine undecylenate, referred to as GS-1, that elicits potent antimicrobial activity. Under CLSI test conditions, GS-1 showed effective antibacterial activity against clinical isolates of methicillin-sensitive <i>S. aureus</i> (MSSA), methicillin-resistant <i>S. aureus</i> (MRSA), vancomycin-intermediate <i>S. aureus</i>, and <i>S. pyogenes</i>, with MICs of 0.60–1.26 mg/mL and MBCs of 0.63–5.04 mg/mL, respectively. Fluorescence microscopy revealed GS-1 to elicit antibacterial activity by rapidly permeabilising bacterial membranes and inducing reactive oxygen species formation. Serial exposure of 5 MRSA clinical isolates to sub-lethal doses of GS-1 did not appear to induce resistance. In fact, compared to mupirocin, repeated exposures to GS-1 appeared to sensitise bacteria to GS-1. In an animal model of skin infection, topical GS-1 successfully eradicated MRSA from infected, abraded skin after 6 days of treatment with no signs of toxicity. Finally, repeated topical GS-1 exposure in humans caused no irritation or sensitisation. These results support GS-1 as a potential novel topical antibacterial for the treatment of impetigo and other skin infections.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Skin Microbiota-Derived Extracellular Vesicles and Their Cosmeceutical Possibilities—A Mini Review","authors":"Thangavelu Soundara Rajan,&nbsp;Ramasamy Saiganesh,&nbsp;Madasamy Sivagnanavelmurugan,&nbsp;Francesca Diomede","doi":"10.1111/exd.70073","DOIUrl":"https://doi.org/10.1111/exd.70073","url":null,"abstract":"<p>The human skin hosts a complex ecosystem of microorganisms, collectively termed the skin microbiota. This intricate skin microbial community plays a pivotal role in human health and disease. Microbes interact with the host skin cells and immune cells through microbial products such as metabolites and secreted proteins. Research in recent years has received significant attention towards extracellular vesicles (EVs)—mediated microbe–host communication. In this concise review, we discuss the role of skin microbiota EVs in the regulation and maintenance of functional dermal tissue. The human topical microbiota is predominantly composed of bacteria, with Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes being the predominant phyla. Fungi, particularly Malassezia species, also constitute a significant component of this dermal microbial ecosystem. Nevertheless, research on EVs has primarily focused on a limited number of bacterial and fungal species pertaining to skin, including <i>Staphylococcus aureus</i>, <i>Staphylococcus epidermidis</i>, <i>Propionibacterium acnes</i>, <i>Lactobacillus plantarum</i> and <i>Malassezia sympodialis</i>. Particularly, EVs derived from <i>Staphylococcus epidermidis</i> and <i>Lactobacillus plantarum</i> show a promising outcome towards the management of skin inflammation and skin ageing. Given the demonstrated ability of EVs to penetrate the skin cells and deliver beneficial compounds, their application in cosmetic and cosmeceutical products remains in its early stages. Accordingly, we also address the need for extensive research, challenges and opportunities to fully harness their potential for skincare regimens.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"51st Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF)","authors":"","doi":"10.1111/exd.70025","DOIUrl":"https://doi.org/10.1111/exd.70025","url":null,"abstract":"","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Stress and Generalised Pustular Psoriasis: Report of d-ROM Measurements in Nine Cases Including Three of Pustular Psoriasis of Pregnancy","authors":"Chisato Tawada,&nbsp;Yoko Ueda,&nbsp;Yoko Mizutani,&nbsp;Xiaoyu Zang,&nbsp;Kayoko Tanaka,&nbsp;Hiroaki Iwata","doi":"10.1111/exd.70076","DOIUrl":"https://doi.org/10.1111/exd.70076","url":null,"abstract":"<p>Reactive oxygen species (ROS) are involved in the pathogenesis of generalised pustular psoriasis (GPP), but this involvement has not been fully elucidated. We performed the diacron-reactive oxygen metabolite (d-ROM) test and the biological antioxidant potential (BAP) test on sera from nine patients with active GPP who were hospitalised and treated at our hospital, including three patients with pustular psoriasis of pregnancy (PPP). The serum d-ROM and BAP levels were evaluated before treatment and at 1 month of treatment. We also performed immunostaining of 4-hydroxy-2-nonenal (4-HNE) in skin tissues. In the GPP patients, the average d-ROM levels were significantly reduced at 1 month of treatment (reduced to 343.0 ± 82.1 U.Carr from 423.2 ± 95.0 U.Carr, <i>p</i> = 0.005). The Generalised Pustular Psoriasis Area and Severity Index (GPPASI) score correlated with d-ROM levels (<i>r</i> = 0.57, <i>p</i> = 0.10), suggesting that those levels reflect the disease severity. In normal pregnancy, d-ROM values are known to increase from mid-term to late-term. The d-ROM values increased when GPP worsened in the case of PPP. Immunohistochemical staining of 4-HNE was positive for subcorneal pustules, neutrophils, and for the cytoplasm of epidermal keratinocytes, especially in upper epidermal layers. Our findings indicate that 4-HNE may play an important role in GPP and PPP.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing UV and Diesel Cutaneous Damage and Evaluating the Protective Role of a Topical Antioxidant Mixture Containing Vitamin C, E and Ferulic Acid","authors":"John Ivarsson,&nbsp;Alessandra Pecorelli,&nbsp;Anna Guiotto,&nbsp;Mariaurea Matias Souza,&nbsp;Hina Choudhary,&nbsp;Patricia Brieva,&nbsp;Francesca Ferrara,&nbsp;Giuseppe Valacchi","doi":"10.1111/exd.70069","DOIUrl":"https://doi.org/10.1111/exd.70069","url":null,"abstract":"<p>Cutaneous tissue is one of the main targets of outdoor stressors, and nowadays, the effect of pollution on skin conditions and premature skin ageing has been well correlated, although the exact effect that different pollutants have on the skin has not been well defined, especially when compared to other stressors. Among the air pollutants, UV radiation and particulate matter (PM) have been found among the most aggressive in terms of skin damage, inducing oxinflammatory responses, promoting degradation of extracellular matrix (ECM) components, and compromising the cutaneous defensive barrier. Topical application of technologies able to prevent oxidative damage is still one of the best approaches to protect our skin, and considering the well-known antioxidant network, application of an antioxidant mixture is more recommended than a single compound. In the present study, human skin explants were exposed every day for 4 days to diesel particles (DEE) or to UV after the daily pre-treatment with a topical application of a commercially available antioxidant mixture (AOX Mix), containing 15% ascorbic acid, 0.5% ferulic acid and 1% tocopherol. Oxidative stress markers such as 4-hydroxynonenal, skin barrier proteins such as involucrin, filaggrin, claudin-1 and desmocollin-1, resilience markers such as elastin and tropoelastin, and the levels of Type I and Type III collagens were assessed. Topical application was able to prevent most of the damage induced by the outdoor stressors, confirming that daily protection is needed to prevent cutaneous premature ageing.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Darier's Disease by Mitochondrial DNA Insertion Causing Nonsense Mutations: In Silico Prediction of a Pathophysiological Mechanism to a Novel Mutation","authors":"Haruna Shintani,&nbsp;Yasuaki Ikuno,&nbsp;Hiraku Kokubu,&nbsp;Shino Fujimoto,&nbsp;Akihiko Yamaguchi,&nbsp;Toshifumi Takahashi,&nbsp;Akiko Arakawa,&nbsp;Yukie Kande,&nbsp;Hayato Naka-Kaneda,&nbsp;Noriki Fujimoto","doi":"10.1111/exd.70070","DOIUrl":"https://doi.org/10.1111/exd.70070","url":null,"abstract":"<p>Darier's disease (DD) is an autosomal dominant genetic disorder caused by mutations in <i>ATP2A2</i>. Several cases with nonsense <i>ATP2A2</i> mutations presented mild-to-moderate phenotypes despite the presumed larger deletion sizes of the ATP2A2 protein. Here, we report a case of severe DD caused by a nonsense mutation with a mitochondrial DNA (mtDNA) insertion despite the smaller presumed deletion size of the ATP2A2 protein. In silico analyses of genomic lesions forming non-B DNA structures and sequence homology indicated the contingency of this DNA insertion. Analysis of the three-dimensional structure of the protein predicted no structural disturbance by this insertion. However, the QGRS Mapper algorithm predicted ectopic G-quadruplex formation in the inserted genome, which may possibly reduce <i>ATP2A2</i> transcription. Consistent with this hypothetical mechanism and possible nonsense-mediated mRNA decay, we identified downregulation of the mtDNA-inserted <i>ATP2A2</i>, which may partially contribute to the severe phenotype in this case. The mtDNA insertions into the human genome are reported to rarely occur, especially in cancers, and only a handful of mtDNA insertions causing genetic diseases are described. This study is the first report to identify mtDNA insertion as a cause of genetic disease in dermatology and demonstrates its pathophysiological mechanism through in silico analyses.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}