The allergy gene: how a mutation in a skin protein revealed a link between eczema and asthma

Ichthyosis vulgaris is a common genetic skin disorder characterized by dry, scaly skin. About 1% of the European population have the full presentation of ichthyosis vulgaris; up to 10% have a milder, subclinical form. Atopic eczema is the most common, inflammatory skin condition, affecting 20% of children. It is often accompanied by a number of other allergies, including atopic asthma. Atopic eczema is a complex trait, where predisposing genes in combination with environmental stimuli produce the disease. Recently, we reported the first loss-of-function genetic mutations in the filaggrin gene as the cause of ichthyosis vulgaris. We noted people with ichthyosis vulgaris also have atopic eczema (and vice versa) and that the filaggrin gene sits in a known atopic eczema susceptibility locus. We went on to confirm that filaggrin mutations, carried by up to 10% of the population, are the major genetic predisposing factor for atopic eczema and the various allergies associated with atopic eczema. Filaggrin is a highly abundant protein expressed in the uppermost part of the epidermis that is critical to the formation and hydration of the stratum corneum—the outermost dead cell layers responsible for the barrier function of the skin. Filaggrin deficiency leads to a “leaky” skin barrier that allows higher than normal water loss (explaining the dry, scaly skin), as well as allowing entry of allergens through the epidermis where they trigger inflammatory and allergic immune responses (atopic eczema and allergies). This work has placed the skin barrier at the center stage of eczema and allergy research and has kick-started new therapy development programs aimed at repairing or enhancing skin-barrier function as a means of treating or preventing these very common diseases.