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Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed., Competing Interests: Declaration of Competing Interest Authors have declared that no conflict of interest exist., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Among genodermatoses, trichothiodystrophies (TTDs) are a rare genetically heterogeneous group of syndromic conditions, presenting with skin, hair, and nail abnormalities. An extra-cutaneous involvement (craniofacial district and neurodevelopment) can be also a part of the clinical picture. The presence of photosensitivity describes three forms of TTDs: MIM#601675 (TTD1), MIM#616390 (TTD2) and MIM#616395 (TTD3), that are caused by variants afflicting some components of the DNA Nucleotide Excision Repair (NER) complex and with more marked clinical consequences. In the present research, 24 frontal images of paediatric patients with photosensitive TTDs suitable for facial analysis through the next-generation phenotyping (NGP) technology were obtained from the medical literature. The pictures were compared to age and sex-matched to unaffected controls using 2 distinct deep-learning algorithms: DeepGestalt and GestaltMatcher (Face2Gene, FDNA Inc., USA). To give further support to the observed results, a careful clinical revision was undertaken for each facial feature in paediatric patients with TTD1 or TTD2 or TTD3. Interestingly, a distinctive facial phenotype emerged by the NGP analysis delineating a specific craniofacial dysmorphic spectrum. In addition, we tabulated every single detail within the observed cohort. The novelty of the present research includes the facial characterization in children with the photosensitive types of TTDs through the 2 different algorithms. This result can become additional criteria for early diagnosis, and for subsequent targeted molecular investigations as well as a possible tailored multidisciplinary personalized management., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Skin inflammation and photosensitivity are common in lupus erythematosus (LE) patients, and ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) patients. Type I interferons (IFN) are upregulated in LE skin after UV exposure; however, the mechanisms to explain UVB-induced inflammation remain unclear. Here, we demonstrated that UVB irradiation-induced activation of human endogenous retroviruses (HERVs) plays a major role in the immune response. UVB-induced HERV-associated dsRNA transcription and subsequent activation of the innate antiviral RIG-I/MDA5/IRF7 pathway led to downstream transcription of interferon-stimulated genes, which promotes UVB-induced apoptosis and proliferation inhibition in keratinocytes through RIG-I and MDA5 pathways. Our findings indicate that UVB irradiation induces HERV-dsRNA overexpression, and the dsRNA-sensing innate immunity pathway promotes type I IFN production, which may be a potential mechanism of skin inflammatory response and skin lesion of SLE/DLE., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Interleukin- (IL-) 33 contributes to various inflammatory processes. IL-33/ST2 activation participates in systemic lupus erythematous via binding to the receptor of Suppression of Tumorigenicity 2 protein (ST2). However, whether IL-33/ST2 interferes with the nosogenesis of cutaneous lupus erythematosus (CLE) has not been reported so far. Herein, we proposed to disclose the impacts on IL-33/ST2 activation and Ro60 on CLE and their potential implications in the photosensitization of CLE cells. IL-33, ST2, and Ro60 in CLE patients' skin lesions were detected. Murine keratinocytes stimulated with or without IL-33 were irradiated by ultraviolet B (UVB), and the levels of Ro60 and inflammation markers were determined. Keratinocytes were cocultured with J774.2 macrophages and stimulated with IL-33 for analysis of chemostasis. The results identified that IL-33, ST2, and downstream inflammation markers were significantly upregulated in CLE lesions with Ro60 overexpression. Additionally, IL-33 treatment promoted the upregulation of Ro60 induced by UVB treatment in murine keratinocytes. Moreover, IL-33 stimulates keratinocytes to induce macrophage migration via enhancing the generation of the chemokine (C-C motif) ligands 17 and 22. Meanwhile, the silencing of ST2 or nuclear factor-kappa B (NF- κ B) suppression abolished IL-33-induced upregulation of Ro60 in keratinocytes. Similarly, the inhibition of SOX17 expression was followed by downregulation of Ro60 in keratinocytes following IL-33 stimulation. In addition, UVB irradiation upregulated SOX17 in keratinocytes. Conclusively, the IL-33/ST2 axis interferes with Ro60-regulated photosensitization via activating the NF- κ B- and PI3K/Akt- and SOX17-related pathways., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yitian Song et al.)

Kindler syndrome (KS) was first described by Theresa Kindler in 1954, and since then > 60 pathogenic variants have been identified in the FERMT1 gene for KS. Most FERMT1 variants associated with KS are null variants. We present the case of a child with poikilodermic changes on the forehead and cheeks, who was found to have a homozygous c.1676G>A mutation. To our knowledge, this is the first report of this mutation in a family with KS., (© 2022 British Association of Dermatologists.)

Photodermatosis is an abnormal skin inflammatory reaction to light. The major classifications of photodermatoses are idiopathic photodermatoses, photodermatoses due to exogenous or endogenous agents, photo-exacerbated dermatoses, and photosensitive genodermatoses. In this chapter, we focus on idiopathic photodermatoses and drug-related photodermatoses and emphasize on the epidemiology and immunogenetic backgrounds. Idiopathic photodermatoses, a spectrum of diseases with abnormal responses to ultraviolet radiation (UVR), include polymorphous light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, and solar urticaria. Young people are more susceptible to most idiopathic photodermatoses except for chronic actinic dermatitis. Interestingly, idiopathic photodermatoses exhibit different characteristics between Caucasians and Asians. For example, the average age of Asian actinic prurigo patients is older than that of Caucasians in which genetic backgrounds or Fitzpatrick skin type might play a role. Drug-induced photodermatoses can be classified into phototoxic and photoallergic drug reactions. Certain drug-induced photodermatoses may mimic other dermatoses. For instance, drug-induced lupus erythematosus (LE) should be considered if an old man is diagnosed with LE but had a poor response to standard treatments., (© 2022. Springer Nature Switzerland AG.)

Background: Inherited genetic erythropoietic protoporphyria (EPP) is characterized by a photosensitive rash that emerges during infancy or early childhood. Acquired EPP can erupt at any age, even during adulthood, and is associated with hematological disorders. A third, less-studied type of EPP is also inherited but appears later in life (during adulthood)., Purpose: To evaluate the characteristics of inherited genetic late-onset (IGLO) EPP., Methods: A systematic comprehensive search of the literature was conducted using PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases. Studies describing patients with IGLO EPP were included. Additionally, we present an index case of a patient, treated at our clinic in whom inherited genetic EPP was diagnosed at age 21 years., Results: The search yielded 1514 citations. Five publications were eligible for review. Along with our case, 7 patients (4 males) were included in the analysis. Mean age at disease onset was 34.2 years (range 18-69, median 30). Most patients presented with mild pruritus and rash in a photosensitive distribution. Mean level of free erythrocyte protoporphyrin IX (FEP) was 8.6 μmol/L. A mutant ferrochelatase gene (FECH) in trans to a hypomorphic FECH allele was found in 3 of the 4 patients who underwent genetic testing., Conclusion: We describe the distinct features of IGLO EPP. This work emphasizes that a diagnosis of inherited genetic EPP should not be ruled out in adults with new-onset photosensitive manifestations., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Photosensitivity is a skin reaction disorder mediated by phototoxic and/or photoallergic mechanisms. The accumulation of porphyrins is generally considered to induce phototoxicity. ATP-binding cassette subfamily G member 2 (ABCG2) has been identified as a transporter of porphyrins and its common variants-p.Gln126Ter (rs72552713) and p.Gln141Lys (rs2231142)-reportedly decrease the function of porphyrin transport in vitro; however, the physiological importance of ABCG2 as a porphyrin transporter remains to be fully elucidated. We herein investigated whether ABCG2 dysfunction could lead to porphyrin accumulation and photosensitivity in Japanese subjects, and found it to be significantly correlated with erythrocyte protoporphyrin levels (P = 0.012). This appears to be the first clinical finding of ABCG2 dysfunction-associated protoporphyrin accumulation in humans. We divided the patients into a chronic actinic dermatosis (CAD) group and a non-CAD group. CAD was diagnosed based on the criteria of reduced minimal erythema doses to ultraviolet B (UVB) and/or ultraviolet A (UVA). The non-CAD group was composed of patients who exhibited normal reactions to UVB and UVA on phototesting, but had histories of recurrent erythema/papules on sun-exposed areas. Estimated ABCG2 function according to ABCG2 genotypes in the non-CAD group was significantly lower than in the general Japanese population (P = 0.045). In contrast, no difference was found in ABCG2 function between the CAD group and the general population, suggesting that ABCG2 dysfunction might be a genetic factor in non-CAD patients with clinical photosensitivity. In this context, genetic dysfunction of ABCG2 might be an overlooked pathological etiology of "photosensitivity of unknown cause."

Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin plays a central role in regulating human pigmentation and reducing the genotoxicity of UV by activating DNA repair and antioxidant defenses. For the development of a hMC1R-targeted photoprotection strategy, we designed tetra- and tripeptide agonists with modifications that provide the necessary lipophilicity and hMC1R selectivity to be effective drugs. These peptides proved to be superior to most of the existing analogs of the physiological tridecapeptide α-melanocortin because of their small size and high hMC1R selectivity. Testing on primary cultures of human melanocytes showed that these peptides are highly potent with prolonged stimulation of melanogenesis, enhanced repair of UV-induced DNA photoproducts, and reduced apoptosis. One of the tripeptides, designated as LK-514 (5), with a molecular weight of 660 Da, has unprecedented (>100,000) hMC1R selectivity when compared with the other melanocortin receptors hMC3R, hMC4R, and hMC5R, and increases pigmentation (sunless tanning) in a cultured, three-dimensional skin model. These new analogs should be efficacious in preventing skin cancer, including melanoma, and treatment of skin disorders, such as vitiligo and polymorphic light eruptions., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially affected his ears, nose, feet, and the genital and ocular mucosa, leading to significant depigmentation, scarring, contractures and mutilation. The whole of the trunk and limbs were involved at the time of presentation, with the exception of some islands of spared skin on the proximal thighs, legs, nipples and external genitalia. Electron microscopy revealed a split in the sublamina densa with the absence of anchoring fibrils, suggestive of dystrophic epidermolysis bullosa (EB). Immunofluorescence antigen mapping demonstrated a broad reticulate pattern of staining with collagen IV, VII, and laminin 332 in the floor of the blister, suggestive of Kindler syndrome. Next-generation sequencing revealed a de novo heterozygous missense mutation (a variant of unknown significance) in exon 22 of the phospholipase-C gamma 2 gene (PLCG2), which resulted in a substitution of serine by asparagine at codon 798 (p.Asp798Ser), a result that was validated using Sanger sequencing. The child was diagnosed with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. The cutaneous and corneal erosions, inflammation and scarring of this magnitude, and the eventual result of death have not been described previously for the PLAID/APLAID spectrum previously. In conclusion, this was an unusual acquired autoinflammatory severe EB-like disease that may be associated with de novo PLCG2 mutation., (© 2021 British Association of Dermatologists.)

Background: There are three major types of genetic cutaneous porphyrias (GCP): erythropoietic protoporphyria (EPP), variegate porphyria (VP), and hereditary coproporphyria (HCP). Scarce data are available regarding their impact on patients' quality of life in the Mediterranean region., Purpose: To describe the cutaneous features of GCP in Israel., Methods: An established nationwide cohort of patients with GCP diagnosed during 1988-2019 was surveyed by telephone for cutaneous features of GCP. Impact on quality of life was assessed using the Dermatology Life Quality Index., Results: Of the 95 patients with GCP, 71 (75%) completed the survey (21 HCP; 40 VP; 10 EPP). All EPP patients reported cutaneous symptoms compared with 58% of VP and 5% of HCP (P < .001). Mean age at symptom onset was 7 ± 6 years in EPP and 25 ± 15 years in VP (P < .001). Photosensitivity was the most common symptom in EPP (90%). In VP photosensitivity (52%), blistering (52%) and scarring (74%) were all common symptoms. In both VP and EPP, the dorsal hands/forearms were the most affected regions (≥96%), and in ≥ 78%, symptoms occurred on an almost daily basis. All EPP patients changed their lifestyle due to cutaneous symptoms vs 57% in VP. Major effect on quality of life was observed among EPP patients compared with a moderate effect in VP. No treatment was effective in EPP, while phototherapy and moisturizers were effective in 5 of 7 (71%) VP patients., Conclusion: This study sheds light on the cutaneous features of the GCP, which have a substantial effect on patients' quality of life., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The epidermal growth factor receptors EGFR and HER2 are the main targets for tyrosine kinase inhibitors (TKIs). The quinazoline derivative lapatinib (LAP) is used since 2007 as dual TKI in the treatment of metastatic breast cancer and currently, it is used as an oral anticancer drug for the treatment of solid tumors such as breast and lung cancer. Although hepatotoxicity is its main side effect, it makes sense to investigate the ability of LAP to induce photosensitivity reactions bearing in mind that BRAF (serine/threonine-protein kinase B-Raf) inhibitors display a considerable phototoxic potential and that afloqualone, a quinazoline-marketed drug, causes photodermatosis. Metabolic bioactivation of LAP by CYP3A4 and CYP3A5 leads to chemically reactive N-dealkylated (N-LAP) and O-dealkylated (O-LAP) derivatives. In this context, the aim of the present work is to explore whether LAP and its N- and O-dealkylated metabolites can induce photosensitivity disorders by evaluating their photo(geno)toxicity through in vitro studies, including cell viability as well as photosensitized protein and DNA damage. As a matter of fact, our work has demonstrated that not only LAP, but also its metabolite N-LAP have a clear photosensitizing potential. They are both phototoxic and photogenotoxic to cells, as revealed by the 3T3 NRU assay and the comet assay, respectively. By contrast, the O-LAP does not display relevant photobiological properties. Remarkably, the parent drug LAP shows the highest activity in membrane phototoxicity and protein oxidation, whereas N-LAP is associated with the highest photogenotoxicity, through oxidation of purine bases, as revealed by detection of 8-Oxo-dG.

Chronic actinic dermatitis (CAD) is a photoallergic skin disease with complicated pathogenesis. However, skin barrier dysfunction may be involved according to clinical manifestation. To investigate the mechanism of CAD barrier dysfunction, noninvasive detection of skin barrier and small RNA sequencing were carried out. Quantitative real-time PCR (qRT-PCR) was used to evaluate the expression levels of hsa-miR-31-3p and CLDN1. The correlation between hsa-miR-31-3p and CAD severity was explored. Further, dual-luciferase reporter assay was performed to identify the relationship between hsa-miR-31-3p and CLDN1. In addition, expression of hsa-miR-31-3p was detected after ultraviolet (UV) irradiation. Influences of hsa-miR-31-3p on primary human keratinocytes barrier were assessed by FITC-Dextran permeability assay. Moreover, western blot was used to detect the expression of claudin-1, filaggrin, loricrin and involucrin. Our results showed that transepidermal water loss (TEWL) significantly increased in CAD, while stratum corneum hydration (SCH) significantly decreased. The expression of hsa-miR-31-3p was up-regulated in CAD while CLDN1 was down-regulated. Hsa-miR-31-3p was correlated with TEWL, UV-MED (minimal erythema dose) and clinical severity scores of CAD (CSS-CAD). Dual-luciferase reporter assay confirmed that hsa-miR-31-3p targeted the 3'UTR region of CLDN1. Moreover, hsa-miR-31-3p was induced by UVB (0-30 mJ/cm 2 ) and UVA (0-4 J/cm 2 ). Furthermore, overexpression of hsa-miR-31-3p increased FITC-Dextran flux of primary human keratinocytes and reduced the expression of claudin-1, filaggrin, loricrin and involucrin. In conclusion, we demonstrated that hsa-miR-31-3p induced by UV was correlated with CAD severity, which played an important role in regulating keratinocytes permeability barrier through targeting CLDN1., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling was accomplished by employing an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), which revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Of particular interest, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3-9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby elucidating a potential new therapeutic strategy to combat AMD., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility., Methods: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome., Results: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population., Conclusions: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis., (© 2020 Wiley Periodicals, Inc.)

Background: Erythropoietic protoporphyria (EPP) is a semi-dominantly inherited porphyria presenting with photosensitivity during early childhood. Acquired EPP has been reported; however, data regarding this rare disorder are scarce., Purpose: To evaluate the characteristics of acquired EPP., Methods: A comprehensive search of PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases was performed by three reviewers. Studies describing patients with acquired EPP were included. Additionally, we present an index case of a 26-year-old patient who acquired clinically and biochemically typical EPP in association with myelodysplastic syndrome (MDS)., Results: We included 20 case reports describing 20 patients. Most (80%) patients were male of mean age 58 ± 13 years. In all patients, acquired EPP was associated with hematological disease, most commonly MDS (85%) followed by myeloproliferative disease (10%). In 86% of cases, hematological disease led to abnormality or somatic mutation in chromosome 18q (the locus of the ferrochelatase gene). The mean erythrocyte protoporphyrin IX concentration was very high (4286 μg/dL). Most (90%) patients presented with photosensitivity, 20% experienced blistering, and 25% presented with hepatic insufficiency, both uncommon in EPP. In 55% of patients, hematological disease was diagnosed after occurrence of cutaneous symptoms. Beta-carotene led to partial control of symptoms in 5 patients and resolution in another patient. Azacitidine treatment of MDS led to resolution of cutaneous symptoms in three patients., Conclusion: We present the distinct features of acquired EPP and highlight that any patient presenting with new-onset photosensitivity, irrespective of age should be evaluated for porphyria., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders., Objectives: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC., Methods: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies., Results: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB., Conclusions: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: UV-sensitive syndrome (UV S S) is a rare autosomal recessive genodermatosis characterised by photosensitivity, and hyperpigmentation, freckling, and dryness of sun exposed areas. In contrast to other photosensitivity disorders, affected patients show no predisposition to cutaneous melanoma or neurological dysfunction. UV S S results from a defect in the transcription-coupled nucleotide excision repair (TC-NER) mechanism. UV S S can be caused by mutations in the genes ERCC8, ERCC6, and UVSSA., Objective: To determine the underlying genetic cause of UV S S and its functional consequences in nine members of two large, unrelated consanguineous pedigrees from Pakistan., Methods: Genomic DNA from one affected member of each family was subjected to whole exome sequencing. The identified mutation was then validated via Sanger sequencing using samples from all available family members. Molecular cloning and mammalian cell cultures were used for the translation and localisation of wild type (WT) and mutant constructs., Results: A novel homozygous nonsense mutation, (c.1040G>A [p.(Trp347*)]), was detected in exon 6 of the UVSSA gene in both families. Sanger sequencing revealed co-segregation of the nonsense mutation with the UV S S phenotype. Immunoblotting revealed the anticipated 81kDa band for the WT construct, and a truncated protein of around 39kDa for the mutant. In mutant samples, immunofluorescence revealed mislocalisation of UVSSA from the nucleus to the cytoplasm., Conclusions: This is the first report of UV S S in the Pakistani population and the fourth report of a disease-causing mutation in UVSSA. The study broadens the UVSSA mutational spectrum, and contributes to functional understanding of truncated UVSSA proteins., (Copyright © 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Kindler Syndrome (KS) is a rare genodermatosis characterized by skin fragility, skin atrophy, premature aging and poikiloderma. It is caused by mutations in the FERMT1 gene, which encodes kindlin-1, a protein involved in integrin signalling and the formation of focal adhesions. Several reports have shown the presence of non-melanoma skin cancers in KS patients but a systematic study evaluating the risk of these tumors at different ages and their potential outcome has not yet been published. We have here addressed this condition in a retrospective study of 91 adult KS patients, characterizing frequency, metastatic potential and body distribution of squamous cell carcinoma (SCC) in these patients. SCC developed in 13 of the 91 patients., Results: The youngest case arose in a 29-year-old patient; however, the cumulative risk of SCC increased to 66.7% in patients over 60 years of age. The highly aggressive nature of SCCs in KS was confirmed showing that 53.8% of the patients bearing SCCs develop metastatic disease. Our data also showed there are no specific mutations that correlate directly with the development of SCC; however, the mutational distribution along the gene appears to be different in patients bearing SCC from SCC-free patients. The body distribution of the tumor appearance was also unique and different from other bullous diseases, being concentrated in the hands and around the oral cavity, which are areas of high inflammation in this disease., Conclusions: This study characterizes SCCs in the largest series of KS patients reported so far, showing the high frequency and aggressiveness of these tumors. It also describes their particular body distribution and their relationship with mutations in the FERMT-1 gene. These data reinforce the need for close monitoring of premalignant or malignant lesions in KS patients.

Introduction: Pallister-Killian Syndrome (PKS) (OMIM #601803) is a rare genetic disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. Epilepsy is a frequent concern in PKS patients., Methods: we report 3 PKS patients, with early-onset myoclonic epilepsy and photosensitivity. In these children, we analysed epileptic history and the EEG phenotype., Results: Epilepsy onset was in the first 2 years of life in all patients and in 2 of them myoclonic seizures were the only seizure type. In all children photosensitivity was observed and myoclonic seizures were mainly related to low-frequency (1-6 Hz) intermittent photic stimulation. Levetiracetam was effective and well tolerated in the 2 treated patients., Conclusions: early-onset myoclonic epilepsy is a possible clinical manifestation of PKS. Low-frequency photosensitivity is a peculiar bioelectrical marker in these children., (Copyright © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Glutathione S-transferases (GSTs) play a critical role in cellular protection against oxidative damage. Polymorphisms in three major GST loci have been described. A number of studies have looked for an association between GSTs and skin diseases., Purpose: To ascertain the possibility that polymorphisms in the GSTM1, GSTT1, and GSTP1 genes may predict the development of photo-induced and non-photo-induced drug eruptions., Methods: A cohort of 40 patients with drug eruptions, 10 of whom had developed a photo-induced drug reaction, and matched controls (116 for GSTM1 and GSTT1, 120 for GSTP1) were studied. Genotyping was conducted using direct sequencing and polymerase chain reaction., Results: The GSTP1 Val/Val genotype was significantly associated with non-photosensitive drug eruptions (OR = 3.64, P value = 0.038), whereas associations observed between GSTP1, GSTM1, GSTT1 polymorphisms and photosensitive drug eruptions did not reach statistical significance., Conclusions: Variations in GSTP1 may affect the risk to develop non-photo-induced drug eruptions. These results warrant confirmatory studies in a larger patient sample., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Kindler syndrome is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding t kindlin-1. Kindlin-1 localizes to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of Kindler syndrome show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective integrin activation, cell adhesion, and migration. However, roles for kindlin-1 beyond integrin activation remain poorly defined. In this study we show that skin and keratinocytes from Kindler syndrome patients have significantly reduced expression levels of the EGFR, resulting in defective EGF-dependent signaling and cell migration. Mechanistically, we show that kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner and that formation of this complex is required for EGF-dependent migration. We further show that kindlin-1 acts to protect EGFR from lysosomal-mediated degradation. This shows a new role for kindlin-1 that has implications for understanding Kindler syndrome disease pathology., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Recent GWAS studies, mostly performed in populations of North European origin, have identified the genetic loci associated with pigmentation, sun sensitivity, freckling and skin cancer susceptibility. Here, we aimed at addressing the genetic determinants of sunlight sensitivity in Spain, a southern European population., Methods: Nine SNPs located in 8 pigmentation-related genes (IRF4, TYR, ASP, HERC2, OCA2, BNC2, SLC24A4 and SLC45A2) were genotyped in 456 Spaniards. Additionally, the complete sequence of the MC1R gene was obtained, testing each nonsynonymous mutation supported by the classification as R or r alleles. A standardised questionnaire was used to collect demographic characteristics, pigmentation and sun sensitivity traits, as well as sun exposure habits., Results: MC1R R alleles and IRF4 rs12203592 were significantly associated with sunlight sensitivity at the Bonferroni-corrected level (P-value < 4.54 × 10 -3 ). Genetic variants in SLC45A2 (rs16891982) and HERC2 (rs12913832) were also found to be significantly associated with skin photosensitivity in our Spanish sample. Interaction analysis using the MDR method revealed epistatic effects when these four variants were considered together., Conclusion: MC1R, IRF4, HERC2 and SLC45A2 play a significant role in skin sensitivity to sunlight in the Spanish population. Moreover, interaction among these four loci seems to modulate the ability of the skin to respond to UV radiation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

OBJECTIVE To identify the genetic cause for congenital photosensitivity and hyperbilirubinemia (CPH) in Southdown sheep. ANIMALS 73 Southdown sheep from a CPH research flock and 48 sheep of various breeds from commercial flocks without CPH. PROCEDURES Whole-genome sequencing was performed for a phenotypically normal Southdown sheep heterozygous for CPH. Heterozygous variants within Slco1b3 coding exons were identified, and exons that contained candidate mutations were amplified by PCR assay methods for Sanger sequencing. Blood samples from the other 72 Southdown sheep of the CPH research flock were used to determine plasma direct and indirect bilirubin concentrations. Southdown sheep with a plasma total bilirubin concentration < 0.3 mg/dL were classified as controls, and those with a total bilirubin concentration ≥ 0.3 mg/dL and signs of photosensitivity were classified as mutants. Sanger sequencing was used to determine the Slco1b3 genotype for all sheep. Genotypes were compared between mutants and controls of the CPH research flock and among all sheep. Protein homology was measured across 8 species to detect evolutionary conservation of Slco1b. RESULTS A nonsynonymous mutation at ovine Chr3:193,691,195, which generated a glycine-to-arginine amino acid change within the predicted Slco1b3 protein, was significantly associated with hyperbilirubinemia and predicted to be deleterious. That amino acid was conserved across 7 other mammalian species. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested a nonsynonymous mutation in Slco1b3 causes CPH in Southdown sheep. This disease appears to be similar to Rotor syndrome in humans. Sheep with CPH might be useful animals for Rotor syndrome research.

Background: Cockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8 / CSA or ERCC6 / CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS., Methods and Results: We assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-phenotype relationships could be made, patients were more likely to have severe clinical features if the mutation was downstream of the PiggyBac insertion in intron 5 of ERCC6/CSB than if it was upstream. Also a higher proportion of severely affected patients was found with mutations in ERCC6/CSB than in ERCC8/CSA ., Conclusion: By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective The objective of this paper is to investigate the association of clinical manifestations and laboratory parameters between familial systemic lupus erythematosus (SLE) and sporadic SLE. Methods All relevant literature was retrieved from the PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) databases. The qualities of these studies were evaluated using a modified version of the Newcastle-Ottawa scale. The characteristics and clinical manifestations of involved individuals were extracted from each study. Pooled odds ratio (OR) was calculated using the random effects-method, and the heterogeneity between studies was quantified using the I 2 statistic. Results Of 330 studies identified by the search strategy, six were included in this review. In total, 733 cases were familial SLE and 1405 were sporadic SLE. Analysis revealed that photosensitivity, nephritis and thrombocytopenia were negatively associated with familial SLE, with OR (95% CI) values of 0.73 (0.60-0.89), 0.72 (0.59-0.88) and 0.75 (0.57-0.98), respectively. Conclusions Photosensitivity, thrombocytopenia and renal involvement could be more common in non-familial SLE, which should be further confirmed by well-designed studies with large populations.

Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains the balance of mitochondrial redox status by generating NADPH as a reducing factor, which is used to reduce oxidized antioxidant proteins and oxidized glutathione. Therefore, the role of IDH2 is crucial in organs that are easily influenced by reactive oxygen species (ROS) or mechanical damage. Humans are constantly exposed to ultraviolet (UV) radiation throughout their lifetime, which can cause various cutaneous diseases, such skin carcinoma, dermatitis, and sunburn. ROS play an important role in the initial step of these diseases; therefore, IDH2 deficient mice (Idh2 -/- ) could be a useful model to investigate UV-mediated skin damage. When we exposed the dorsal skin of Idh2 -/- mice to UVB, pyrimidine dimers and (6-4) photoproducts (6-4PPs), marker of photoproducts generated by UVB, were found in the dermis of the knockout mice. Increased collagen degradation, apoptosis, inflammation, and ROS levels in the dermis were also observed. These results indicated that UVB could reach the dermis by penetrating the epidermis. We then attempted to determine how the epidermis was breached, and observed a decrease in the expression level of ΔNp63, a major protein required for epidermis generation, in the Idh2 -/- mice. The mito-TEMPO supplement significantly ameliorates UVB-induced damage in the skin of Idh2 -/- mice. In the present study, we provided a role for IDH2 in protection against UVB-induced skin damage and a new connection between IDH2 and ΔNp63., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Kindler syndrome is a rare, autosomal recessive genodermatosis, caused by mutations in the FERMT1 gene. It is thought to be primarily a skin disease, but other organs may also be involved. We report a case of a novel mutation of FERMT1 gene in a patient with a probable new phenotype of Kindler syndrome, including colitis and primary sclerosing cholangitis. A 42-year-old man, born to first cousin parents, was referred to our outpatient dermatology clinic with an unknown dermatosis since birth. He presented with neonatal blistering and developed photosensitivity and changes in skin pigmentation during childhood. Since the age of 20, he has had regular follow-up in the gastroenterology clinic, owing to esophageal stenosis, ulcerative colitis, and primary sclerosing cholangitis. Clinical examination revealed jaundice, poikiloderma, diffuse cigarette paper-like atrophy on dorsal surfaces of the hands, and palmoplantar hyperkeratosis. Skin biopsy showed epidermal atrophy covered by orthokeratotic hyperkeratosis. DNA molecular analysis revealed FERMT1 homozygous mutation c.1179G&gt;A, p.W393X, which has not been reported before. The intestinal phenotype of Kindler syndrome has already been defined previously. However, to the best of our knowledge, no other case of primary sclerosing cholangitis in a patient with Kindler syndrome has been reported.

Epidermolysis bullosa (EB) is caused by mutations in as many as 19 distinct genes. We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction. The NGS panel was applied to a cohort of 92 consanguineous families of unknown subtype of EB. In one family, a homozygous donor splice site mutation in CD151 (NM&#95;139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids. Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151. Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis. Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures. The patient also had history of nephropathy with proteinuria. Collectively, the results suggest that biallelic loss-of-function mutations in CD151 underlie an autosomal recessive mechano-bullous disease with systemic features. Thus, CD151 should be considered as the 20th causative, EB-associated gene., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks., Case Presentation: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient's cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus., Conclusions: Patients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable.

Background: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study., Methods: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families., Results: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes., Conclusion: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders., (© 2017 The International Society of Dermatology.)

Background: Actinic lentigos (AL) are benign hyperpigmented skin lesions associated with photoageing. Despite their high prevalence, biological mechanisms driving their formation remain unclear., Objectives: To provide new insights about the physiopathology of AL through a comprehensive description of their histological and molecular features., Methods: Quantitative analysis of dermoscopic images was used to select AL containing elongated patterns, predicted to display a highly deformed dermal-epidermal junction (DEJ), on the back of the hands of 15 Caucasian women. Biopsies from lesional and adjacent nonlesional (NL) areas were processed for histological analysis or gene expression profiling., Results: Histological staining confirmed a drastic deformation of the DEJ in AL, with deep epidermal invaginations into the dermis. Although the melanin content was significantly higher in AL compared with NL epidermis, the distribution of melanocytes along the DEJ was unchanged. Transcriptomic analysis revealed a signature of 529 genes differently expressed in AL vs. NL skin. Alteration of epidermal homeostasis was confirmed by the dysregulation of keratinocyte proliferation and differentiation markers. Surprisingly, canonical genes involved in melanogenesis were not significantly modulated in AL. A striking finding was the overexpression of a large group of genes involved in dermal extracellular matrix organization and remodelling. Dermal alterations were confirmed by immunolabellings on AL and NL sections., Conclusions: Drastic disorganization of the cutaneous structure in AL is accompanied by a specific molecular signature revealing alterations in both epidermal and dermal compartments. In particular, our results suggest that local modifications of the dermal extracellular matrix might contribute to hyperpigmentation in AL., (© 2017 British Association of Dermatologists.)

Sunlight exposure induces signalling pathways leading to the activation of melanin synthesis and tanning response. MicroRNAs (miRNAs) can regulate the expression of genes involved in pigmentation pathways by binding to the complementary sequence in their 3'untranslated regions (3'UTRs). Therefore, 3'UTR SNPs are predicted to modify the ability of miRNAs to target genes, resulting in differential gene expression. In this study, we investigated the role in pigmentation and sun-sensitivity traits, as well as in melanoma susceptibility, of 38 different 3'UTR SNPs from 38 pigmentation-related genes. A total of 869 individuals of Spanish origin (526 melanoma cases and 343 controls) were analysed. The association of genotypic data with pigmentation traits was analysed via logistic regression. Web-based tools for predicting the effect of genetic variants in microRNA-binding sites in 3'UTR gene regions were also used. Seven 3'UTR SNPs showed a potential implication in melanoma risk phenotypes. This association is especially noticeable for two of them, rs2325813 in the MLPH gene and rs752107 in the WNT3A gene. These two SNPs were predicted to disrupt a miRNA-binding site and to impact on miRNA-mRNA interaction. To our knowledge, this is the first time that these two 3'UTR SNPs have been associated with sun-sensitivity traits. We state the potential implication of these SNPs in human pigmentation and sensitivity to sunlight, possibly as a result of changes in the level of gene expression through the disruption of putative miRNA-binding sites., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H 2 O 2 ) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The clinical and electroencephalographic features of a canine generalized myoclonic epilepsy with photosensitivity and onset in young Rhodesian Ridgeback dogs (6 wk to 18 mo) are described. A fully penetrant recessive 4-bp deletion was identified in the DIRAS family GTPase 1 ( DIRAS1 ) gene with an altered expression pattern of DIRAS1 protein in the affected brain. This neuronal DIRAS1 gene with a proposed role in cholinergic transmission provides not only a candidate for human myoclonic epilepsy but also insights into the disease etiology, while establishing a spontaneous model for future intervention studies and functional characterization.

Chronic actinic dermatitis (CAD), a photosensitive dermatosis, is characterized by inflammatory lesions, especially on sun-exposed skin. However, its pathogenesis remains unclear. In this study, second-generation RNA sequencing and comprehensive bioinformatics analyses of mRNAs and long noncoding RNAs (lncRNAs) were performed to determine the transcriptome profiles of patients with CAD. A total 6889 annotated lncRNAs, 341 novel lncRNAs, and 65091 mRNAs were identified. Interestingly, patients with CAD and healthy controls showed distinct transcriptome profiles. Indeed, 198 annotated (81.48%) and 45 novel (18.52%) lncRNAs were differentially expressed between the two groups. GO, KEGG, and RGSEA analyses of lncRNAs showed that inflammatory and immune response related pathways played crucial roles in the pathogenetic mechanism of CAD. In addition, we unveiled key differentially expressed lncRNAs, including lncRNA RP11-356I2.4 which plays a role probably by regulating TNFAIP3 and inflammation. qRT-PCR data validated the differentially expressed genes. The newly identified lncRNAs may have potential roles in the development of CAD; these findings lay a solid foundation for subsequent functional exploration of lncRNAs and mRNAs as therapeutic targets for CAD.

The availability of whole-exome sequencing has revolutionized the study of genetic disease in recent years, particularly in dermatology, where clinical phenotypes are readily recognized. As this technology becomes increasingly affordable and accessible, questions are emerging regarding the clinical and ethical responsibilities of physicians who determine variants underlying disease, especially with regard to children, for whom treatment may be warranted and clinical course improved based on a known genotype. These responsibilities are accentuated in the developing countries, which harbor most consanguineous populations and thus bear the brunt of monogenic genodermatoses. Although many genetic disorders are identified in these populations, limited educational and clinical infrastructure rarely offers opportunities to improve the course of disease. Here we report a genetic study that illustrates these challenges., (© 2016 Wiley Periodicals, Inc.)

Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Psoriasis commonly responds beneficially to UV radiation from natural sunlight or artificial sources. Therapeutic mechanisms include the proapoptotic and immunomodulating effects of UV, affecting many cells and involving a variety of pro- and anti-inflammatory cytokines, downregulating the Th17/IL-23 response with simultaneous induction of regulatory immune cells. However, exposure to UV radiation in a subset of psoriasis patients leads to exacerbation of the disease. We herein shed light on the predisposing factors of photosensitive psoriasis, including genetics (such as HLA-Cw*0602 or CARD14), gender and coexisting photodermatoses such as polymorphic light eruption (PLE) in the context of potential molecular mechanisms behind therapeutic photoresponsiveness or photoaggravation. UV-induced damage/pathogen-associated molecular patterns, damage to self-coding RNA (signalling through Toll-like receptors), certain antimicrobial peptides and/or inflammasome activation may induce innate immunity, leading to psoriasis at the site of UV exposure when there is concomitant, predisposing resistance against UV-induced suppression of the adaptive immune response (like in PLE) that otherwise would act to reduce psoriasis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hereditary photodermatoses are a spectrum of rare photosensitive disorders that are often caused by genetic deficiency or malfunction of various components of the DNA repair pathway. This results clinically in extreme photosensitivity, with many syndromes exhibiting an increased risk of cutaneous malignancies. This review will focus specifically on the syndromes with malignant potential, including xeroderma pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome. The typical phenotypic findings of each disorder will be examined and contrasted, including noncutaneous identifiers to aid in diagnosis. The management of these patients will also be discussed. At this time, the mainstay of therapy remains strict photoprotection; however, genetic therapies are under investigation., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Photodermatoses associated with defective DNA repair are a group of photosensitive hereditary skin disorders. In this review, we focus on diseases and syndromes with defective nucleotide excision repair that are not accompanied by an increased risk of cutaneous malignancies despite having photosensitivity. Specifically, the gene mutations and transcription defects, epidemiology, and clinical features of Cockayne syndrome, cerebro-oculo-facial-skeletal syndrome, ultraviolet-sensitive syndrome, and trichothiodystrophy will be discussed. These conditions may also have other extracutaneous involvement affecting the neurologic system and growth and development. Rigorous photoprotection remains an important component of the management of these inherited DNA repair-deficiency photodermatoses., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)