Locus 1q21 Gene Expression Changes in Atopic Dermatitis Skin Lesions: Deregulation of Small Proline-Rich Region 1A

Abstract

Background: Discovery of the significant impact of filaggrin (FLG) mutations on the genetic predisposition to atopic dermatitis (AD) focused attention on the 1q21 locus, where not only FLG but also other epidermal genes are located. In the present study, we compared 1q21 gene expression in lesional versus nonlesional AD skin. Methods: A real-time quantitative PCR analysis of 10 1q21 genes, selected on the basis of a previous microarray study, was performed in skin biopsies from 33 individuals with AD. Three alternative pathway keratins were also evaluated. Results: In chronic AD skin lesions, we observed an increase in RNA encoding involucrin, S100 calcium-binding proteins A2 and A7–A9 and small proline-rich region (SPRR) proteins 1A and 2C, with fold changes ranging from 2.0 for S100A2 to 15.4 for S100A8 (p < 0.001, Bonferroni corrected), in parallel to the overexpression of the alternative pathway keratins 6A, 6B and 16. The loricrin (LOR) expression level was significantly decreased in lesional AD skin (fold change 0.5; p < 0.01). The expression of the majority of 1q21 genes and alternative keratins was closely correlated; however, for SPRR1A (and SPRR2C) in lesional skin, the correlation with other genes was lost. Conclusions: We hypothesize that the deregulated increase in SPRR1A expression in chronic atopic skin lesions reflects an insufficient rise in SPRR transcripts, unable to compensate for the lack of LOR and thus contributing to the persistence of chronic AD skin lesions. Turning off the stress response in the skin may be regarded as a goal in the treatment of AD skin lesions, and SPRR genes might be targets for such an approach.

Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis

“…4, 30, 31 This is supported by GWAS, which identified genetic association of epithelial cell genes including TSLP/WDR36 , IL33 and its receptor ST2 ( IL1RL1 ) with atopic sensitization and various allergic diseases. 32 GWAS identified filaggrin, a skin tissue-enriched gene, as strongly genetically associated with atopic dermatitis.…”

Real-time PCR quantification of the canine filaggrin orthologue in the skin of atopic and non-atopic dogs: a pilot study

“…In some humans with AD, these mutations may be associated with decreased immunostaining of the filaggrin protein in both lesional and non-lesional skin [13,14]. On the other hand, changes in FLG mRNA expression in human atopic skin are not so clear [13,15-17]. The only study that has analysed mRNA and protein expression simultaneously in human atopic patients determined that the decrease in expression in lesional skin was mostly caused by inflammatory sub-products (interleukins), and that the presence of mutations in the FLG gene did not significantly affect mRNA levels in non-lesional skin [13].…”

Skin Barrier Defects in Atopic Dermatitis

“…Also, the staining patterns of corneodesmosomal proteins have been shown to be abnormally diffuse (51). In addition, loricrin and involucrin are expressed at lower levels in AD skin as compared with healthy skin (50, 52, 53). In a mouse model, combined deficiencies in the scaffold proteins of the cornified envelope, involucrin, envoplakin and periplakin, resulted in hyperkeratosis, as well as decreased lipid content and reduced proteases resulting in defective filaggrin processing.…”