What is new and hot in genetics of human atopic dermatitis: shifting paradigms in the landscape of allergic skin diseases.

The immunologic abnormalities in patients with allergic skin diseases occur as a consequence of primary defects residing within the epidermis, suggesting an association between skin barrier dysfunction and immune abnormalities (1). The skin barrier is located in the uppermost layers of the epidermis, the stratum corneum, with important elements: in-tracellular keratin filaments, intercellular lipids, and a cornified cell envelope. It plays a vital role in all terrestrial forms of life, due to prevention of fluid loss and protection from microbial and allergen invasion. Functional lack of epidermal enzymes and structural skin proteins compromises skin barrier integrity and function. These deficiencies can even induce local changes in the expression of various inflammatory mediators, suggesting the direct immunologic role of the epidermis in the pathogenesis of allergic skin diseases (1). Primary isolated epidermal defects can result in allergy. Filaggrin (FLG), involucrin, and lo-ricrin are among the most important structural proteins. Also, lipids play very important role, as well as some enzymes, such as serine proteases. Netherton syndrome is classic example of autosomal recessive disorder due to loss-of-function mutations in SPINK5, the gene encoding the SP inhibitor lymphoepithelial Kazal-type trypsin inhibitor (LEKTI) (2). Most importantly , mutations of filaggrin (FLG) gene, an essential component of the skin barrier, are associated with ichthyosis vulgaris and atopic dermatitis (AD). AD is inflammatory skin disease caused by inherited skin barrier deficiency, with mutations in FLG predispos-ing to development of AD. AD has highly heritable complex trait; however, environmental influences also play a role in triggering the atopic diathesis (3,4). Genome-wide association studies in AD have identified several susceptibility loci; however, the major and only functionally characterized genetic factor is FLG, which encodes skin barrier protein FLG (4). FLG is one of the most prominent genes responsible for barrier defect. FLG has been identified as a major locus causing skin barrier deficiency; however, not all patients with AD have this mutation, so AD cannot be explained by FLG mutation (3,4). Support for barrier deficiency initiating AD came from flaky tail mice, which have frameshift mutation in FLG and also carry an unknown gene, the Matt gene, causing a matted hair phenotype (1,4,5). This phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Sasaki et al. and Saunders et al. report successful delineation of the genetic basis of the …