A homozygous frameshift mutation in the murine filaggrin gene facilitates enhanced percutaneous allergen priming

Loss-of-function mutations in the filaggrin gene (FLG), cause the semi-dominant keratinizing disorder, ichthyosis vulgaris1, and convey major genetic risk to atopic dermatitis/eczema, eczema-associated asthma2,3 and other allergic phenotypes5. Several low frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of ~9% in Europe4. Here we report a 1-bp deletion mutation, 5303delA, highly analogous to common human FLG mutations, within the murine flg gene in the spontaneous mouse mutant flaky tail (ft). Importantly, we demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate ft as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.