RESUMO
Loss-of-function mutations in arachidonate lipoxygenase 12B (ALOX12B) are an important cause of autosomal recessive congenital ichthyosis (ARCI). 12R-lipoxygenase (12R-LOX), the protein product of ALOX12B, has been proposed to covalently bind the corneocyte lipid envelope (CLE) to the proteinaceous corneocyte envelope, thereby providing a scaffold for the assembly of barrier-providing, mature lipid lamellae. To test this hypothesis, an in-depth ultrastructural examination of CLEs was performed in ALOX12B-/- human and Alox12b-/- mouse epidermis, extracting samples with pyridine to distinguish covalently attached CLEs from unbound (ie, noncovalently bound) CLEs. ALOX12B--/- stratum corneum contained abundant pyridine-extractable (ie, unbound) CLEs, compared with normal stratum corneum. These unbound CLEs were associated with defective post-secretory lipid processing, and were specific to 12R-LOX deficiency, because they were not observed with deficiency of the related ARCI-associated proteins, patatin-like phospholipase 1 (Pnpla1) or abhydrolase domain containing 5 (Abhd5). These results suggest that 12R-LOX contributes specifically to CLE-corneocyte envelope cross-linking, which appears to be a prerequisite for post-secretory lipid processing, and provide insights into the pathogenesis of 12R-LOX deficiency in this subtype of ARCI, as well as other conditions that display a defective CLE.
Assuntos
Araquidonato 12-Lipoxigenase/genética , Ictiose/diagnóstico por imagem , Metabolismo dos Lipídeos , Proteínas/metabolismo , Animais , Araquidonato 12-Lipoxigenase/deficiência , Araquidonato 12-Lipoxigenase/metabolismo , Epiderme/ultraestrutura , Feminino , Humanos , Queratinócitos/ultraestrutura , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mutação , Piridinas/metabolismo , Pele/ultraestruturaRESUMO
The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.
Assuntos
Dermatite Atópica , Ictiose Vulgar , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Proteínas Filagrinas , Humanos , Ictiose Vulgar/genética , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Água/metabolismoRESUMO
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors. In skin, PPARs modulate inflammation, lipid synthesis, keratinocyte differentiation and proliferation and thus are important for skin barrier homeostasis. Accordingly, PPAR expression is altered in various skin conditions that entail epidermal barrier impairment, that is atopic dermatitis (AD) and psoriasis. Using human epidermal equivalents (HEEs), we established models of acute epidermal barrier impairment devoid of immune cells. We assessed PPAR and cytokine expression after barrier perturbation and examined effects of keratinocyte-derived cytokines on PPAR expression. We show that acetone or SDS treatment causes graded impairment of epidermal barrier function. Furthermore, we demonstrate that besides IL-1ß and TNFα, IL-33 and TSLP are highly relevant markers for acute epidermal barrier impairment. Both SDS- and acetone-mediated epidermal barrier impairment reduce PPARG expression levels, whereas only SDS enhances PPARD expression. In line with findings in IL-1ß and TNFα-treated HEEs, abrogation of IL-1 signalling restores PPARG expression and limits the increase of PPARD expression in SDS-induced epidermal barrier impairment. Thus, following epidermal barrier perturbation, keratinocyte-derived IL-1ß and partly TNFα modulate PPARG and PPARD expression. These results emphasize a role for PPARγ and PPARß/δ in acute epidermal barrier impairment with possible implications for diseases such as AD and psoriasis.
Assuntos
Epiderme/metabolismo , Interleucina-1beta/metabolismo , Queratinócitos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Dermatopatias/metabolismo , Células Cultivadas , Regulação para Baixo , Humanos , Regulação para CimaRESUMO
Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients.
Assuntos
Regulação da Expressão Gênica , Ictiose/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Queratinócitos/metabolismo , Modelos Biológicos , Criança , Pré-Escolar , Feminino , Proteínas Filagrinas , Humanos , Ictiose/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Lactente , Queratinócitos/patologia , MasculinoRESUMO
Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.
Assuntos
Quimiocinas/metabolismo , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Inflamação/prevenção & controle , Neutrófilos/metabolismo , Inibidores de Proteases/metabolismo , Adolescente , Adulto , Animais , Humanos , Mediadores da Inflamação/metabolismo , Ionomicina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NADPH Oxidases/genética , Neutrófilos/efeitos dos fármacos , Periodontite/metabolismo , Proteólise , Acetato de Tetradecanoilforbol/farmacologia , Ácido Úrico/farmacologiaRESUMO
HINTERGRUND: Ichthyosen sind eine heterogene Gruppe von Krankheiten, deren klinische Klassifizierung schwierig ist. Hier wird die Ichthyosekohorte eines Expertisezentrums für Genodermatosen im Detail beschrieben. PATIENTEN UND METHODIK: Eingeschlossen wurden Patienten mit klinisch oder genetisch bestätigter Ichthyose, die zwischen 2004 und 2017 untersucht und in einer Datenbank aufgenommen wurden. Krankheitsbeginn, Phänotyp, Histologie, Komorbiditäten und Familienanamnese wurden detailliert beschrieben. Bei den genetisch getesteten Patienten wurden Jahr und Methode der genetischen Testung protokolliert und die Prävalenz der unterschiedlichen Autosomal-rezessive-kongenitale Ichthyose (ARCI)-Gene und -Phänotypen, die Prävalenz der syndromalen Ichthyosen und die Genotyp-Phänotyp-Korrelationen analysiert. ERGEBNISSE UND METHODIK: Von den insgesamt 198 eingeschlossenen Patienten wurden 151 genetisch getestet. 81 Patienten hatten eine Ichthyosis vulgaris (IV), 43 eine X-chromosomale Ichthyose (XLI), 38 eine ARCI, 9 eine keratinopathische Ichthyose (KPI) und ein Patient eine Exfoliative Ichthyose. 26 Patienten litten an einer syndromalen Ichthyose. Im Vergleich zu den syndromalen Ichthyosen wurde bei den häufigen Ichthyosen (IV, XLI) und KPI eine gute Phänotyp-Genotyp-Korrelation beobachtet. In 91 % der ARCI-Patienten konnte die exakte Diagnose durch genetische Testung gestellt werden. Lediglich bei 33 % der Patienten mit syndromaler Ichthyose bestand vor der genetischen Testung ein Verdacht auf die tatsächliche Diagnose. In 86 % der Fälle wurde eine kausale Mutation nachgewiesen. SCHLUSSFOLGERUNGEN: Die Arbeit beschreibt das Spektrum der Ichthyosen an einem Expertisezentrum und zeigt, dass für diese Gruppe die genetische Testung von Genodermatosen ein diagnostischer Standard werden sollte.
RESUMO
BACKGROUND: Ichthyoses are a heterogeneous disease group, which makes clinical classification challenging. An ichthyosis cohort at a center for genodermatoses is presented in detail. PATIENTS AND METHODS: Patients with clinically and/or genetically confirmed ichthyosis seen from 2004 to 2017 and listed in a database were included. Disease onset, phenotype, histology, comorbidities and family history were described in detail. In genetically tested patients, the prevalence of various ARCI genes, ARCI phenotypes and syndromic ichthyoses, as well as genotype-phenotype correlation and year/method of genetic testing was assessed. RESULTS: Of all 198 patients who were included in the cohort, 151 were genetically tested. 81 had ichthyosis vulgaris, 43 X-linked ichthyosis, 38 autosomal recessive congenital ichthyosis (ARCI), 9 keratinopathic ichthyosis (KPI) and one exfoliative ichthyosis. 26 individuals suffered from syndromic ichthyoses. A good genotype-phenotype correlation was observed for common ichthyoses and KPI; the correlation was less good in syndromic ichthyoses. In 91 % of ARCI patients an accurate diagnosis was obtained by genetic testing. In only 33 % of syndromic ichthyoses was the definitive diagnosis suspected before genetic testing, which revealed a causative mutation in 86 % of cases. CONCLUSION: This study describes the spectrum of ichthyoses in a center of expertise and shows that genetic testing should become a diagnostic standard for this disease group.
Assuntos
Testes Genéticos , Ictiose/genética , Fenótipo , Adolescente , Áustria , Feminino , Genótipo , Humanos , Ictiose/classificação , Ictiose/diagnóstico , Ictiose/patologia , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Mutação , Estudos RetrospectivosRESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathogenesis. Although regulatory T cells (Tregs) have previously been studied in AD, their role remains controversial, likely owing to patient heterogeneity. Thus, we recruited adult AD patients and age-matched healthy controls, and assessed their filaggrin (FLG) genotype, serum IgE level, and eczema area and severity index (EASI). We found increased proportions of all circulating Treg subpopulations in AD patients. Moreover, we show positive correlations between circulating Tregs and serum IgE FLG null mutations limited the expansion of both memory and effector Tregs and enhanced that of recently thymus-emigrated Tregs. Furthermore, proportions of circulating Th2- or Th17-Tregs but not Th1-Tregs were increased in AD patients, and accentuated by FLG null mutations, thereby mimicking the immune deviation observed in Th cell populations. Moreover, ICOS+ Tregs showed reduced production of interleukin-10, suggesting impaired immunosuppression in AD. The level of demethylation of FOXP3i1, which reflects the stability of FOXP3 expression, was similar in the blood and skin of AD patients and healthy controls. Overall, these results show that Tregs may participate into AD pathogenesis and that FLG null mutations exert further modifications on specific subpopulations of circulating Tregs.
Assuntos
Biomarcadores/sangue , Dermatite Atópica/imunologia , Mutação com Perda de Função , Proteínas S100/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Estudos de Casos e Controles , Dermatite Atópica/sangue , Dermatite Atópica/genética , Dermatite Atópica/patologia , Proteínas Filagrinas , Seguimentos , Humanos , PrognósticoRESUMO
Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.
Assuntos
Complemento C1r/genética , Complemento C1s/genética , Síndrome de Ehlers-Danlos/genética , Deleção de Genes , Mutação de Sentido Incorreto , Periodontite/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Síndrome de Ehlers-Danlos/diagnóstico , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Exoma , Feminino , Loci Gênicos , Humanos , Masculino , Linhagem , Periodontite/diagnóstico , Conformação Proteica , Adulto JovemRESUMO
BACKGROUND: It has recently been suggested that patients with moderate to severe atopic dermatitis (AD) may profit from anti-interleukin (IL)-12/-23 p40 therapy. OBJECTIVE: We sought to assess the immunologic effects of ustekinumab treatment on AD skin and to correlate them with the clinical efficacy of this drug. METHODS: We investigated the course of 3 patients with severe AD who were administered 45 mg of subcutaneous ustekinumab over a period of 16 weeks. Clinical scores and skin biopsy specimens, taken at baseline and at week 8, were used to assess changes in disease severity. RESULTS: All patients showed a gradual improvement of the disease, achieving a 50% reduction in the Eczema Area and Severity Index score by week 16. Immunohistology of skin biopsy specimens revealed a significant decrease in the degree of epidermal hyperplasia/proliferation and the number of infiltrating dermal T cells, dendritic cells, and mast cells after treatment. Using quantitative real-time polymerase chain reaction of lesional skin, we found a clear reduction of T-helper 2-/22-associated molecules after therapy. LIMITATIONS: The small number of patients (n = 3) limits efficacy analysis and warrants prospective placebo-controlled studies in larger patient cohorts. CONCLUSION: Blocking IL-12/-23 p40 could be beneficial for a subgroup of patients with severely infiltrated AD.
Assuntos
Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Fármacos Dermatológicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Th2/metabolismo , Ustekinumab/farmacocinética , Adulto , Contagem de Linfócito CD4 , Citocinas/genética , Citocinas/metabolismo , Fármacos Dermatológicos/uso terapêutico , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Células de Langerhans/efeitos dos fármacos , Masculino , Mastócitos/efeitos dos fármacos , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Linfócitos T Citotóxicos/efeitos dos fármacos , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Ustekinumab/uso terapêuticoRESUMO
Although keratosis pilaris (KP) is common, its etiopathogenesis remains unknown. KP is associated clinically with ichthyosis vulgaris and atopic dermatitis and molecular genetically with filaggrin-null mutations. In 20 KP patients and 20 matched controls, we assessed the filaggrin and claudin 1 genotypes, the phenotypes by dermatoscopy, and the morphology by light and transmission electron microscopy. Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype. Major histologic and dermatoscopic findings of KP were hyperkeratosis, hypergranulosis, mild T helper cell type 1-dominant lymphocytic inflammation, plugging of follicular orifices, striking absence of sebaceous glands, and hair shaft abnormalities in KP lesions but not in unaffected skin sites. Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. All these features were independent of filaggrin genotype. Moreover, ultrastructure of corneodesmosomes and tight junctions appeared normal, immunohistochemistry for claudin 1 showed no reduction in protein amounts, and molecular analysis of claudin 1 was unremarkable. Our findings suggest that absence of sebaceous glands is an early step in KP pathogenesis, resulting in downstream hair shaft and epithelial barrier abnormalities.
Assuntos
Anormalidades Múltiplas/patologia , Doença de Darier/patologia , Epiderme/anormalidades , Sobrancelhas/anormalidades , Cabelo/anormalidades , Proteínas de Filamentos Intermediários/deficiência , Glândulas Sebáceas/anormalidades , Anormalidades Múltiplas/genética , Adulto , Idoso , Claudina-1/metabolismo , Doença de Darier/genética , Dermoscopia , Desmossomos/metabolismo , Epiderme/ultraestrutura , Sobrancelhas/patologia , Feminino , Proteínas Filagrinas , Genótipo , Cabelo/ultraestrutura , Humanos , Proteínas de Filamentos Intermediários/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Permeabilidade , Fenótipo , Glândulas Sebáceas/patologia , Glândulas Sebáceas/ultraestrutura , Adulto JovemRESUMO
Tight junctions are important for skin barrier function. The tight junction protein claudin 1 (Cldn-1) has been reported to be down-regulated in nonlesional skin of atopic dermatitis (AD) patients. In contrast, we did not observe a significant down-regulation of Cldn-1 in nonlesional skin of the AD cohort used in this study. However, for the first time, a significant down-regulation of Cldn-1 in the upper and lower epidermal layers of lesional skin was detected. In addition, there was a significant up-regulation of Cldn-4 in nonlesional, but not lesional, AD skin. For occludin, no significant alterations were observed. In an AD-like allergic dermatitis mouse model, Cldn-1 down-regulation in eczema was significantly influenced by dermal inflammation, and significantly correlated with hallmarks of eczema (ie, increased keratinocyte proliferation, altered keratinocyte differentiation, increased epidermal thickness, and impaired barrier function). In human epidermal equivalents, the addition of IL-4, IL-13, and IL-31 resulted in a down-regulation of Cldn-1, and Cldn1 knockdown in keratinocytes resulted in abnormal differentiation. In summary, we provide the first evidence that Cldn-1 and Cldn-4 are differentially involved in AD pathogenesis. Our data suggest a role of Cldn-1 in AD eczema formation triggered by inflammation.
Assuntos
Claudina-1/metabolismo , Claudina-4/metabolismo , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Queratinócitos/patologia , Adulto , Regulação para Baixo , Feminino , Humanos , Interleucina-13/genética , Masculino , Pele/metabolismo , Pele/patologiaRESUMO
BACKGROUND: Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. OBJECTIVE: We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. METHODS: Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. RESULTS: No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. CONCLUSIONS: SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.
Assuntos
Dermatite/genética , Desmoplaquinas/genética , Hipersensibilidade/genética , Mutação de Sentido Incorreto/genética , Síndrome de Emaciação/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Dermatite/diagnóstico , Desmogleína 1/genética , Progressão da Doença , Humanos , Hipersensibilidade/diagnóstico , Lactente , Recém-Nascido , Masculino , Linhagem , Estrutura Terciária de Proteína/genética , Pele/patologia , Síndrome de Emaciação/diagnósticoRESUMO
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.
Assuntos
Dermatite Atópica/genética , Predisposição Genética para Doença , Ictiose Vulgar/genética , Proteínas de Filamentos Intermediários/genética , Sequência de Bases , Códon sem Sentido/genética , Epiderme/metabolismo , Proteínas Filagrinas , Mutação da Fase de Leitura/genética , Frequência do Gene , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Irlanda , Dados de Sequência Molecular , Análise de Sequência de DNA , População BrancaRESUMO
Corneocytes in mammalian stratum corneum are surrounded by a monolayer of covalently bound ω-OH-ceramides that form the corneocyte (-bound) lipid envelope (CLE). We review here the structure, composition, and possible functions of this structure, with insights provided by inherited and acquired disorders of lipid metabolism. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.