A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming

Abstract

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.

Bleomycin Hydrolase Is Regulated Biphasically in a Differentiation- and Cytokine-dependent Manner

“…It is involved in homocysteinethiolactone metabolism (17), antigen presentation (18,19), and amyloid-␤-peptide clearance (20,21). Interestingly, BH knockout mouse shows analogous phenotypes to those of filaggrindeficient flaky tail ft/ft mouse, including ichthyosis and atopylike phenotype and tail constriction (22)(23)(24). These findings indicate that BH has a role in maintaining epidermal barrier function.…”

Flaky Tail Mouse as a Novel Animal Model of Atopic Dermatitis: Possible Roles of Filaggrin in the Development of Atopic Dermatitis

“…Flg ft mice were outcrossed onto B6 mice at Jackson Laboratory (Bar Harbor, ME, USA) (Lane, 1972, Presland, et al, 2000 (Note: Although this strain was crossed with B6, it is not a B6 congenic strain but rather a hybrid stock that is probably semi-inbred). Homozygous Flg ft mice have dry, flaky skin which expresses reduced amounts of profilaggrin mRNA and abnormal profilaggrin protein that is not processed to filaggrin monomers (Fallon, et al, 2009, Presland, et al, 2000. Recently, it has been revealed that the gene responsible for the characteristic phenotype of Flg ft mice is a single nucleotide deletion at position 5303 in exon 3 (5303delA) of the profilaggrin gene, resulting in a frameshift mutation and premature truncation of the predicted protein product.…”

“…The copy number of the filaggrin repeat contained within this gene varies depending on the background strain. This mutant occurs in an allele with 16 copies of the filaggrin repeat (Fallon, et al, 2009). Flg ft mouse carries double gene mutation, Flg and matted (ma) in which the locations of the mutated genes are within close linkage to one another (Lane, 1972).…”

A programme of research to set priorities and reduce uncertainties for the prevention and treatment of skin disease

“…This may be enough to stop irritants and allergens, which can initiate inflammation and an allergic response. In addition, both human and mouse studies suggest skin barrier improvement may prevent IgE sensitisation 191,205,206 and, if so, this approach may also prevent allergic asthma and food allergy.…”