Subject(s)
Cellulitis/complications , Eosinophilia/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Skin/pathology , Antineoplastic Agents/administration & dosage , Biopsy , Cellulitis/pathology , Eosinophilia/pathology , Fusion Proteins, bcr-abl/genetics , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Skin/drug effects , Treatment OutcomeSubject(s)
Asian People/genetics , Asthma/genetics , Dermatitis, Atopic/genetics , Intermediate Filament Proteins/genetics , Adolescent , Adult , Aged , Asian People/statistics & numerical data , Asthma/ethnology , Dermatitis, Atopic/ethnology , Filaggrin Proteins , Genetic Predisposition to Disease/ethnology , Humans , Middle Aged , Young AdultABSTRACT
Mutations in the gene-encoding filaggrin (FLG), a key molecule involved in skin barrier function, have been shown to be a major predisposing factor for atopic dermatitis (AD; eczema). To elucidate the pathomechanisms underlying filaggrin-related AD, we investigated stratum corneum (SC) hydration and transepidermal water loss (TEWL) as parameters of barrier function in AD patients harboring FLG mutations compared to AD patients without any FLG mutation. In filaggrin-related AD, SC hydration was both significantly reduced (P<0.01-0.05) and thicker (P<0.01-0.05) than that in healthy controls. TEWL was demonstrably increased in non-filaggrin AD compared to healthy controls (P<0.01-0.05). The objective score of atopic dermatitis (OSCORAD), a disease clinical severity index, significantly correlated with TEWL (r=0.81, P<0.005), SC hydration (r=-0.65, P<0.05), and SC thickness (r=0.59, P<0.05) in filaggrin-related AD. On the contrary, there was no correlation between these parameters and the OSCORAD in non-filaggrin AD. Furthermore, a significant correlation was obtained between the OSCORAD and specific IgE for house dust (r=0.66, P<0.05), mite allergen (r=0.53, P<0.05), and cat dander (r=0.64, P<0.05) in filaggrin-related AD, but not in non-filaggrin AD. All these data suggest that experimentally demonstrable skin barrier defects due to FLG mutations may play a crucial role in the pathogenesis of AD.
Subject(s)
Eczema/metabolism , Epidermis/metabolism , Intermediate Filament Proteins/chemistry , Intermediate Filament Proteins/metabolism , Mutation , Adolescent , Adult , Animals , Case-Control Studies , Child , Female , Filaggrin Proteins , Genotype , Humans , Immunoglobulin E/metabolism , Male , MiceSubject(s)
Hearing Loss, Sensorineural , Ichthyosis , Keratitis , Female , Humans , Middle Aged , SyndromeABSTRACT
Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and shown to be major predisposing factors for atopic dermatitis (AD). However, these studies have been mainly carried out in European populations. In early 2007, we identified two Oriental-specific FLG mutations in four Japanese families with IV and reported that filaggrin mutations were also significant predisposing factors for AD in Japan. However, the frequency of FLG mutations observed in our Japanese AD cohort (5.6%), was much lower than that seen in Europeans (up to 48%). Here, we studied a further seven Japanese families with IV and identified two additional nonsense mutations in FLG, S2889X, and S3296X. We found that more than 20% of patients in our Japanese AD case series carry FLG mutations, and there is significant statistical association between the four mutations and AD (chi(2) P=8.4 x 10(-6); heterozygote odds ratio 7.57, 95% CI 2.84-23.03). These data emphasize that skin-barrier impairment due to reduced filaggrin expression plays an important role in the pathogenesis of AD and sheds further light on the genetic architecture of atopy in Japan.
