Expression signature of epidermolysis bullosa simplex

Abstract

Epidermolysis bullosa simplex (EBS) is a skin disorder resulting from a weakened cytoskeleton of the proliferative compartment of the epidermis, leading to cell fragility and blistering. Although many mutations have been identified in intermediate filament keratins KRT5 and KRT14, detailed pathogenic mechanisms and the way these mutations affect cell metabolism are unclear. Therefore, we performed genomic and transcriptomic study in six Canadian EBS patients and six healthy subjects. We first characterized these patients at the genetic level and identified six pathogenic mutations of which two were novel. Then, we performed an expression microarray analysis of the EBS epidermis tissue to identify potential regulatory pathways altered in this disease. Expression profiling comparisons show that 28 genes are differentially expressed in EBS patients compared to control subjects and 41 genes in severe phenotype patients (EBS-DM) compared to their paired controls. Nine genes involved in fatty acid metabolism and two genes in epidermal keratinization are common altered expressed genes (up regulated) between the two subgroups. These two biological pathways contribute both to the formation of the cell envelope barrier and seem to be defective in the severe EBS phenotype. This study identifies, for the first time, the fatty acid metabolism disruption in EBS.

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

“…4E). Furthermore, only 11 upregulated genes at E18.5 and 18 genes at P0 in Krt1 2/2 skin were common to human EBS patient skin (Bchetnia et al, 2012). Based on these data we conclude that the gene expression signature from Krt1 2/2 mice shows more similarities to human inflammatory skin diseases than to keratin-associated defects in mice and humans (supplementary material Table S3).…”

“…Transcriptome data from AE (E-GEOD-12511), psoriasis (E-GEOD-13355), Krt5 P0 (E-GEOD-7663) and EBS (E-GEOD-28315) were downloaded from the EBI server for the further comparison analysis (Bchetnia et al, 2012;Gudjonsson et al, 2010;Lu et al, 2007;Sääf et al, 2008). For data processing GNU R (www.rproject.org) with the Bioconductor packages (www.bioconductor.org) were used.…”

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes

“…In future studies, investigation of how other types of plectin mutations, such as in EBS Ogna (Walko et al, 2011), and EBS caused by keratin mutations affect nuclear morphology and gene expression will be of great importance. Recent mRNA expression profiling studies, implicating pathways related to interleukins, lipid metabolism and keratinisation, suggest that transcriptional mechanisms might indeed play a role in EBS (Bchetnia et al, 2012;Lu et al, 2007). Ultimately, identifying the impact of altered nuclear mechanics in the pathophysiology of blistering skin diseases could shed new light on our understanding and treatment of these complex and painful conditions.…”

Genetic pathways in disorders of epidermal differentiation

“…In epidermolysis bullosa simplex (EBS), the severity of disease frequently correlates with the site of mutation in KRT5 and KRT14, with mutations in the region responsible for linking the small acidic type I keratins ( KRT1, KRT5 ) to the larger neutral-basic type II keratins ( KRT10, KRT14 ) giving rise to more severe phenotypes due to the overall disturbance of the KIF network [2]. A recent study investigating the genomic changes occurring in EB versus normal skin confirmed recurrent mutations in KRT5 / KRT14 and identified EB gene signatures that point to dysfunction in lipid metabolism as well as epidermal keratinization [4]. EB is also characterized by mutations in various cell adhesion genes, including lamin 332, integrins, and collagen VII recently reviewed in [5].…”