On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis

Abstract

Undisturbed epidermal differentiation is crucial for an intact skin barrier function. The epidermal differentiation complex (EDC) is a cluster of genes on chromosome 1q21 encoding proteins that fulfil important functions in terminal differentiation in the human epidermis, including filaggrin, loricrin, S100 proteins and others. Recently, evidence emerged that variation within EDC genes plays an important role in the pathogenesis of three common skin disorders, ichthyosis vulgaris, atopic dermatitis (AD) and psoriasis. Two loss-of-function mutations in the filaggrin (FLG) gene, R501X and 2282del4, were identified as causative for ichthyosis vulgaris in 15 affected European families, and the mode of inheritance was found to be semidominant. As ichthyosis vulgaris and AD often occur concomitantly in affected individuals, these two mutations were subsequently investigated in AD patients and found to be strongly associated with the disease. Following this first report, seven replication studies have been performed that all confirm an association of these two mutations with AD (or AD subtypes) in several European cohorts. Additionally, two unique loss-of-function mutations in the FLG gene were identified in Japanese ichthyosis vulgaris families and found to be associated with AD in a Japanese cohort. Thus, the FLG mutations are among the most consistently replicated associations for AD. Additionally, linkage analysis has suggested that variation within the EDC might also predispose for psoriasis but the exact susceptibility variation(s) have not yet been elucidated. Taken together, these findings convincingly demonstrate the important role of barrier dysfunction in various common skin disorders.

Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action

“…29 Ichthyosis, atopic dermatitis and predisposition to psoriasis have all been linked to genetic variations within the EDC. 30 The mechanisms by which retinoids regulate genes within the EDC are of interest. The clustering of numerous retinoic-acid responsive genes on 1q21 raises the question as to whether each of these genes is individually transcribed following binding of retinoic acid to its promoter elements or whether retinoic acid affects epigenetic regulation of the EDC through a locus control region, similar to regulation of the β-globin gene locus on chromosome 11p15.5, or by other epigenetic mechanisms.…”

Individual Susceptibility to Occupational Contact Dermatitis

“…Both genes are located within the epidermal differentiation complex on chromosome 1q21, a dense cluster of genes involved in the terminal epidermal differentiation and formation of the stratum corneum 24) . Filaggrin is a protein essential for aggregating keratin filaments.…”

Glycine Receptors are Present in Human Epidermis

“…2c,d, arrows). Since glycine has been reported to influence skin permeability barrier homeostasis [13,14], we wanted to know how GlyR behave in a situation with disturbed epidermal barrier, as can be found on psoriasis or eczema [18,19]. Most notably, we found a striking reduction of GlyR immunoreactivity in specimens of eczema and psoriasis, restricted exactly to the parts of the epidermis covered with parakeratosis (arrow in Fig.…”