On the Role of the Epidermal Differentiation Complex in Ichthyosis Vulgaris, Atopic Dermatitis and Psoriasis

S. Hoffjan; S. Stemmler

Disclosures

The British Journal of Dermatology. 2007;157(3):441-449. 

In This Article

Summary and Introduction

Summary

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.

Introduction

The most important function of the human epidermis is to establish and maintain an effective barrier function that allows transepidermal water loss to a small degree but protects against dehydration.[1] Additionally, the skin also provides a natural barrier against profuse percutaneous absorption of exogenous substances.[1] This barrier function is reached by a complex differentiation process of epidermal cells which develop from mitotically active basal cells into dead, flattened squames in the stratum corneum that are tightly connected to each other and further surrounded by lipid layers.

Defective epidermal differentiation and cornification are observed in various skin disorders, predominantly the ichthyoses, a group of skin diseases characterized by a generalized scaling of the skin.[2] For some of the rare, congenital ichthyoses, mutations in different genes have been identified, and the gene loci as well as the modes of inheritance are very heterogeneous (summarized in reference 2). Yet, for the most common form, ichthyosis vulgaris, the underlying genetic variation was unclear for quite a long time.

Several genes or gene families that encode proteins essential for epidermal differentiation are located within a tight cluster on chromosome 1q21, called the epidermal differentiation complex (EDC). 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. This review gives an overview of the processes that take place during normal epidermal differentiation, describes the organization of the EDC and summarizes the latest findings implicating EDC variation in the pathogenesis of these three diseases.

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