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Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic eczema is a common, chronic, inflammatory skin condition with considerable heterogeneity. South Asian people living in the UK frequently have low serum vitamin D3 (25(OH)D 3 ), and those with atopic disease can present with severe eczema. The association between vitamin D deficiency and eczema severity, and the role of vitamin D supplementation in atopic eczema is inconsistent, and under-researched in people with Asian ancestry., Objectives: This cross-sectional study investigates the association between serum 25(OH)D 3 and eczema severity in a cohort of South Asian children and young adults living in London., Methods: Eligible participants were Bangladeshi children and young adults aged 0-30 years with eczema, living in London and participating in the Tower Hamlets Eczema Assessment study. Data was collected via parent/patient self-reporting, clinical history and examination, and hospital databases. 25(OH)D 3 levels were documented retrospectively, if available, from hospital databases. Eczema severity was classified by Eczema Area and Severity Index (EASI) score less than or greater than 10 (clear-mild vs. moderate-severe). Multivariate logistic regression was used to adjust for confounding factors., Results: 681 participants were included in analyses. 25(OH)D 3 results were available for 49.6% (338/681), 84.3% of which had deficient or insufficient lowest 25(OH)D 3 . Lowest 25(OH)D 3 was inversely correlated with EASI score (Spearman's rank R 2  < 0.001). 26.1% (178/681) had EASI >10 and a lower median lowest and nearest 25(OH)D p . After adjustment for confounding EASI > 10 was significantly associated with a lowest 25(OH)D 3 . After adjustment for confounding EASI > 10 was significantly associated with a lowest 25(OH)D 3  < 25 (OR 3.21, 95%CI 1.35, 8.60), use of mild-moderate potency topical steroid on the face and neck (OR 3.11, 95%CI 1.86, 5.31), calcineurin inhibitor on the face and neck (OR 2.79, 95% CI 1.26, 6.10) and potent - very potent topical steroid on the face and neck (OR2.23, 95%CI 1.02, 4.77) and body (OR 2.11, 95%CI 1.18, 3.87)., Discussion: Vitamin D plays a role in modulation of proteins required for skin barrier function and regulation of the innate immune system, suggesting 25(OH)D 3 deficiency contributes to skin inflammation. This study demonstrates a relationship between 25(OH)D 3 deficiency and worse eczema severity in a cohort of South Asian children and young adults., Competing Interests: Rebecca L. McCarthy: Position funded by Palvella Therapeutics to work on a clinical trial. Unrelated to this work and all funding goes to the university. Edel A. O'Toole: Research funding: Kamari Pharma, Unilever. Consultancy: Azitra Inc, Palvella Therapeutics and Kamari Pharma; Speaker: Almirall. All unrelated to this work and all funding goes to the university., (© 2024 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.

Competing Interests: Conflicts of interest R.L.McC. has held a position funded by Palvella Therapeutics to work on a clinical trial (all unrelated to this work with all funding going to the university. D.G. has been a speaker for Lilly and La Roche-Posay (none applicable to this work). M.T. has been a speaker for AbbVie, Almirall, Eucerin, Janssen and Sanofi (none applicable to this work). E.O’T. has received research funding from Kamari Pharma and Unilever; consultancy fees from Azitra, Palvella Therapeutics and Kamari Pharma; and speaker’s fees from Almirall (all unrelated to this work with all funding going to the university). M.S. declares no conflicts of interest.

Recessive X-linked ichthyosis (RXLI), a genetic disorder caused by deletion or point mutations of the steroid sulfatase ( STS ) gene, is the second most common form of ichthyosis. It is a disorder of keratinocyte cholesterol sulfate retention and the mechanism of extracutaneous phenotypes such as corneal opacities and attention deficit hyperactivity disorder are poorly understood. To understand the pathomechanisms of RXLI, the transcriptome of differentiated primary keratinocytes with STS knockdown was sequenced. The results were validated in a stable knockdown model of STS, to confirm STS specificity, and in RXLI skin. The results show that there was significantly reduced expression of genes related to epidermal differentiation and lipid metabolism, including ceramide and sphingolipid synthesis. In addition, there was significant downregulation of aldehyde dehydrogenase family members and the oxytocin receptor which have been linked to corneal transparency and behavioural disorders respectively, both of which are extracutaneous phenotypes of RXLI. These data provide a greater understanding of the causative mechanisms of RXLI's cutaneous phenotype, and show that the keratinocyte transcriptome and lipidomics can give novel insights into the phenotype of patients with RXLI., Competing Interests: EO has had grant funding from Palvella Therapeutics and Kamari Pharma. She has consulted for Palvella Therapeutics, Kamari Pharma and Azitra Inc. She has had PhD studentships co-funded with GSK and Unilever. She has been a speaker for Almirall. All money goes to the university. MD was employed by Senzo Health Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McGeoghan, Camera, Maiellaro, Menon, Huang, Dewan, Ziaj, Caley, Donaldson, Enright and O’Toole.)

Background: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG)., Objectives: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants., Methods: A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants., Results: There were 506 complete cases available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74-3.67], SH (ME 0.85, 95% CI 0.78-0.96) and TEWL (ME 1.32, 95% CI 1.11-1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91-80.73], improving to 77.99% (73.70-82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02-94.19)., Conclusions: This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively., Competing Interests: Conflicts of interest E.A.O’T. has received research funding paid to the university from Kamari Pharma and Unilever, consulting fees paid to the university from Azitra Inc., Kamari Pharma, Palvella Therapeutics and Timber Pharma unrelated to this work. All other authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid-resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established clustered regularly interspaced short palindromic repeats-Cas9 SGPL1 KO and a lentiviral-induced SGPL1 overexpression (OE) in telomerase reverse-transcriptase immortalised human keratinocytes (N/TERT-1) and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine, and ceramides, while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1&#95;KO, and our gene set enrichment analysis revealed polar opposite differential gene expression between SGPL1&#95;KO and &#95;OE in keratinocyte differentiation and Ca 2+ signaling genesets. SGPL1&#95;KO upregulated differentiation markers, while SGPL1&#95;OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1&#95;KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions. We conclude that SPLIS associated ichthyosis is a multifaceted disease caused possibly by sphingolipid imbalance and excessive S1P signaling, leading to increased differentiation and an imbalance of the lipid lamellae throughout the epidermis., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic eczema (AE) is a chronic relapsing, pruritic disease that greatly affects the child and family's quality of life (QoL). It is usually common and severe among children of Bangladeshi ethnicity., Objectives: This is a cross-sectional quantitative study in patients with AE of Bangladeshi origin, which aims to analyse different components of the family, children and adult quality-of-life indices and their relationship to patient age, sex, eczema severity and distribution, other allergic associations, parental education and socioeconomic level., Methods: Children and young adults of Bangladeshi origin aged 0-30 years, clinically diagnosed with AE were recruited as part of the Tower Hamlets Eczema Assessment project, a clinical phenotyping study of AE in the Bangladeshi population living in East London. Questionnaires completed by children/parents included the Family Dermatology Life Quality Index (FDLQI), Infant's Dermatology Quality of Life (IDQOL) and the Children's Dermatology Life Quality Index (CDLQI). Young adults completed the Dermatology Life Quality Index (DLQI). The disease severity was assessed objectively using the Eczema Area Severity Index (EASI). Patients and parents who did not read or speak English were aided by Bengali/Sylheti-speaking research assistants., Results: Overall, 460 Bangladeshi children and 98 adults with AE were recruited. Burden of care, extra housework and emotional distress were the highest affected domains in parental QoL, while itching and sleep were the highest for children. Significant factors influencing FDLQI score were EASI [marginal effect (ME) 1.01, 95% confidence interval (CI) 1.00-1.03; P = 0.004], age (ME 0.98, 95% CI 0.97-0.99; P = 0.004), extensor eczema distribution (ME 1.25, 95% CI 1.03-1.52; P = 0.023), parental English fluency (ME 1.29, 95% CI 1.10-1.52; P = 0.002) and atopic comorbidities (ME 1.10, 95% CI 1.04-1.17; P = 0.001). Parental socioeconomic class was a nonsignificant factor. IDQOL/CDLQI was influenced significantly by the child's age (ME 0.99, 95% CI 0.97-1.00, P = 0.023), 'nonclear' eczema distribution clusters especially the 'severe extensive' cluster (ME 1.46, 95% CI 1.15-1.84; P = 0.002) and nonsignificantly by EASI and parental English literacy and socioeconomic levels. DLQI was affected significantly by nonclear eczema distribution groups especially 'severe extensive' (ME 2.49, 95% 1.76-3.53; P < 0.001) and nonsignificantly by patient age, and female sex., Conclusions: AE is a chronic disease where many external factors other than disease severity affect QoL of patients and their families, -especially in under-represented minority groups who face different linguistic and cultural barriers., Competing Interests: Conflicts of interest E.O.T. - research funding to university from Kamari Pharma and Unilever, consulting fees to university from Palvella Therapeutics, Azitra Inc, Timber Pharma and Kamari Pharma unrelated to this work. The other authors declare they have no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest Professor O’Toole has received funding for the university from Palvella Therapeutics (consultancy), Timber Pharma (consultancy), and Kamari Pharma (research grant and consultancy). Dr Hansen has received support from Palvella as a principal investigator for a clinical study in pachyonychia. Drs Tan, Steele and Thomas and Ms Schwartz have no conflicts of interest to declare.

Objectives: The gingiva heals at an accelerated rate with reduced scarring when compared to skin. Potential well-studied factors include immune cell number, angiogenesis disparities and fibroblast gene expression. Differential keratinocyte gene expression, however, remains relatively understudied. This study explored the contrasting healing efficiencies of gingival and skin keratinocytes, alongside their differential gene expression patterns., Methods: 3D organotypic culture models of human gingiva and skin were developed using temporarily immortalised primary keratinocytes. Models were wounded for visualisation of re-epithelialisation and analysis of keratinocyte migration to close the wound gap. Concurrently, differentially expressed genes between primary gingival and skin keratinocytes were identified, validated, and functionally assessed., Results: Characterisation of the 3D cultures of gingiva and skin showed differentiation markers that recapitulated organisation of the corresponding in vivo tissue. Upon wounding, gingival models displayed a significantly higher efficiency in re-epithelialisation and stratification versus skin, repopulating the wound gap within 24 hours. This difference was likely due to distinct patterns of migration, with gingival cells demonstrating a form of sheet migration, in contrast to skin, where the leading edge was typically 1-2 cells thick. A candidate approach was used to identify several genes that were differentially expressed between gingival and skin keratinocytes. Knockdown of PITX1 resulted in reduced migration capacity of gingival cells., Conclusion: Gingival keratinocytes retain in vivo superior wound healing capabilities in in vitro 2D and 3D environments. Intrinsic gene expression differences could result in gingival cells being 'primed' for healing and play a role in faster wound resolution., Clinical Significance Statement: The successful development of organotypic models, that recapitulate re-epithelialisation, will underpin further studies to analyse the oral response to wound stimuli, and potential therapeutic interventions, in an in vitro environment., Competing Interests: Conflict of Interest Statement The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Atopic eczema is a common and complex disease. Missing genetic hereditability and increasing prevalence in industrializing nations point toward an environmental driver. We investigated the temporal association of weather and pollution parameters with eczema severity. This cross-sectional clinical study was performed between May 2018 and March 2020 and is part of the Tower Hamlets Eczema Assessment. All participants had a diagnosis of eczema, lived in East London, were of Bangladeshi ethnicity, and were aged <31 years. The primary outcome was the probability of having an Eczema Area and Severity Index score > 10 after previous ambient exposure to commonly studied meteorological variables and pollutants. There were 430 participants in the groups with Eczema Area and Severity Index ≤ 10 and 149 in those with Eczema Area and Severity Index > 10. Using logistic generalized additive models and a model selection process, we found that tropospheric ozone averaged over the preceding 270 days was strongly associated with eczema severity alongside the exposure to fine particles with diameters of 2.5 μm or less (fine particulate matter) averaged over the preceding 120 days. In our models and analyses, fine particulate matter appeared to largely act in a supporting role to ozone. We show that long-term exposure to ground-level ozone at high levels has the strongest association with eczema severity., (Crown Copyright © 2021 Published by Elsevier Inc. on behalf of the Society for Investigative Dermatology.)

Background: Maintaining adequate oxygen delivery (DO 2 ) after major surgery is associated with minimising organ dysfunction. Skin is particularly vulnerable to reduced DO 2 . We tested the hypothesis that reduced perioperative DO 2 fuels inflammation in metabolically compromised skin after major surgery., Methods: Participants undergoing elective oesophagectomy were randomised immediately after surgery to standard of care or haemodynamic therapy to achieve their individualised preoperative DO 2 . Abdominal punch skin biopsies were snap-frozen before and 48 h after surgery. On-line two-dimensional liquid chromatography and ultra-high-definition label-free mass spectrometry was used to characterise the skin proteome. The primary outcome was proteomic changes compared between normal (≥preoperative value before induction of anaesthesia) and low DO 2 (2 after oesophagectomy. Failure to maintain preoperative DO 2 was associated with upregulation of proteins counteracting oxidative stress. Normal DO 2 after surgery was associated with pathways involving leucocyte recruitment and upregulation of an antimicrobial peptidoglycan recognition protein. Immunohistochemistry (n=6 patients) and immunoblots after liver resection (n=12 patients) supported the proteomic findings., Conclusions: Proteomic profiles in serial skin biopsies identified organ-protective mechanisms associated with normal DO 2 after major surgery., Clinical Trial Registration: ISRCTN76894700., Competing Interests: Declarations of interest GLA is an Editor of British Journal of Anaesthesia; and declares consultancy work for GlaxoSmithKline, unrelated to this work., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Periostin, an extracellular matrix macromolecule implicated in tumorigenesis, serves as a prognostic marker for many cancer types. However, there are no data on periostin expression in cutaneous squamous cell carcinoma (cSCC). This study examined periostin expression in patients with cSCC and explored its clincopathological relationship and prognosis. Using immunohistochemistry and ImageJ analysis, we compared periostin expression in 95 cSCCs across a spectrum of cSCC aggressiveness: cSCC in situ (SCCIS) (n = 25), low-risk cSCC (LR-cSCC) (n = 26), high-risk cSCC (HR-cSCC) (n = 38), and cSCC in recessive dystrophic epidermolysis bullosa patients (RDEB cSCC) (n = 6). Immunohistochemistry demonstrated periostin expression within the intra-tumoral stroma but not within tumor cells. Periostin levels significantly (P < 0.001) increased from SCCIS, LR-cSCC, HR-cSCC to RDEB SCC. The stroma of most of the cSCCs we evaluated contained cancer-associated fibroblasts with a myofibroblastic (α -SMA-positive) phenotype. Co-localization of periostin with α-SMA, evidence of fibroblast periostin expression, and absence of keratinocyte or tumor cell periostin expression suggest that, in cSCC, periostin is a product of the peritumoral microenvironment and not the tumor cells themselves. Our data indicate that fibroblast periostin expression is highly correlated with the aggressiveness of cSCC, and may thereby provide a molecular marker that will be useful for subtyping and diagnosing cSCCs according to their biological nature., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases., (Copyright © 2021, American Association for the Advancement of Science.)

Mohamad et al. (2020) describe loss-of-function mutations in SERPINA12 as a cause of diffuse, transgradient palmoplantar keratoderma (PPK). This disorder shares similar clinical features with other PPKs caused by protease overactivity, including erythema, peeling, and exacerbation on water exposure. Understanding this disorder may shed further light on the role of proteases and their inhibitors in epidermal physiology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no satisfactory treatment has been developed. We sought to investigate pathomechanisms of HI that could lead to the identification of new treatments for improving patients' quality of life. In this study, RNA-Seq and functional assays were performed to define the effects of loss of ABCA12 using HI patient skin samples and an engineered CRISPR/Cas9 ABCA12 KO cell line. The HI living skin equivalent (3D model) recapitulated the HI skin phenotype. The cytokines IL-36α and IL-36γ were upregulated in HI skin, whereas the innate immune inhibitor IL-37 was strongly downregulated. We also identified STAT1 and its downstream target inducible nitric oxide synthase (NOS2) as being upregulated in the in vitro HI 3D model and HI patient skin samples. Inhibition of NOS2 using the inhibitor 1400W or the JAK inhibitor tofacitinib dramatically improved the in vitro HI phenotype by restoring the lipid barrier in the HI 3D model. Our study has identified dysregulated pathways in HI skin that are feasible therapeutic targets.

Purpose: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC., Methods: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi-quantification compared tumors and control tissue using IF analysis by ImageJ software., Results: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls., Conclusions: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC.

The terminal domains of suprabasal keratins of the skin epithelium are very resistant to evidence-based structural analysis because of their inherent flexibility and lack of predictable structure. We present a model for the structure and interactions of the head and tail domains of epidermal keratins 1 and 10, based on all-atom 3D simulations of keratin primary amino acid sequences, and tyrosine phosphorylation predictions, extracted from published databases. We observed that keratin 1 and 10 end domains are likely to form a tetrameric terminal domain complex incorporating a reversibly extendable region potentially acting as a molecular spring. This structure is formed by intermolecular stacking of aromatic residues, which would spatially constrain the keratin 1/keratin 10 end domains to allow filament compaction and bundling, whilst also retaining extensibility to ensure flexibility of the keratin filament network in the differentiating epidermis. The tetrameric terminal domain complex model may also help to elucidate the effects of mutations in the end domains of suprabasal keratins and so contribute to understanding of the mechanisms leading to keratinopathies such as striate palmoplantar keratoderma, as reported in this study., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in keratin genes cause a diverse spectrum of skin, hair and mucosal disorders. Cutaneous disorders include epidermolysis bullosa simplex, palmoplantar keratoderma, epidermolytic ichthyosis and pachyonychia congenita. Both clinical and laboratory observations confirm a major role for keratins in maintaining epidermal cell-cell adhesion. When normal tissue homeostasis is disturbed, for example, during wound healing and cancer, keratins play an important non-mechanical role. Post-translational modifications including glycosylation and phosphorylation of keratins play an important role in protection of epithelial cells from injury. Keratins also play a role in modulation of the immune response. A current focus in the area of keratins and disease is the development of new treatments including small inhibitory RNA (siRNA) to mutant keratins and small molecules to modulate keratin expression.

Epidermal wound healing is a complex and highly coordinated process where several different cell types and molecules, such as growth factors and extracellular matrix (ECM) components, play an important role. Among the many proteins that are essential for the restoration of tissue integrity is the metalloproteinase (MMP) family. MMPs can act on ECM and non-ECM components affecting degradation and modulation of the ECM, growth-factor activation and cell-cell and cell-matrix signalling. MMPs are secreted by different cell types such as keratinocytes, fibroblasts and inflammatory cells at different stages and locations during wound healing, thereby regulating this process in a very coordinated and controlled way. In this article, we review the role of MMPs and their inhibitors (TIMPs), as well as the disintegrin and metalloproteinase with the thrombospondin motifs (ADAMs) family, in epithelial wound repair.

Rising levels of ultraviolet radiation (UVR) secondary to ozone depletion are an issue of concern for public health. Skin cancers and intraepidermal dysplasia are increasingly observed in individuals that undergo chronic or excessive sun exposure. Such alterations of skin integrity and function are well established for humans and laboratory animals, but remain unexplored for mammalian wildlife. However, effects are unlikely to be negligible, particularly for species such as whales, whose anatomical or life-history traits force them to experience continuous sun exposure. We conducted photographic and histological surveys of three seasonally sympatric whale species to investigate sunburn and photoprotection. We find that lesions commonly associated with acute severe sun damage in humans are widespread and that individuals with fewer melanocytes have more lesions and less apoptotic cells. This suggests that the pathways used to limit and resolve UVR-induced damage in humans are shared by whales and that darker pigmentation is advantageous to them. Furthermore, lesions increased significantly in time, as would be expected under increasing UV irradiance. Apoptosis and melanocyte proliferation mirror this trend, suggesting that whales are capable of quick photoprotective responses. We conclude that the thinning ozone layer may pose a risk to the health of whales and other vulnerable wildlife.

A large proportion of recessive nonsyndromic hearing loss is due to mutations in the GJB2 gene encoding connexin 26 (Cx26), a component of a gap junction. Within different ethnic groups there are specific common recessive mutations, each with a relatively high carrier frequency, suggesting the possibility of heterozygous advantage. Carriers of the R143W GJB2 allele, the most prevalent in the African population, present with a thicker epidermis than noncarriers. In this study, we show that (R143W)Cx26-expressing keratinocytes form a significantly thicker epidermis in an organotypic coculture skin model. In addition, we show increased migration of cells expressing (R143W)Cx26 compared to (WT)Cx26-overexpressing cells. We also demonstrate that cells expressing (R143W)Cx26 are significantly less susceptible to cellular invasion by the enteric pathogen Shigella flexneri than (WT)Cx26-expressing cells. These in vitro studies suggest an advantageous effect of (R143W)Cx26 in epithelial cells.

Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.