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

TY - JOUR

T1 - A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming

AU - Fallon, Padraic G.

AU - Sasaki, Takashi

AU - Sandilands, Aileen

AU - Campbell, Linda E.

AU - Saunders, Sean P.

AU - Mangan, Niamh E.

AU - Callanan, John J.

AU - Kawasaki, Hiroshi

AU - Shiohama, Aiko

AU - Kubo, Akiharu

AU - Sundberg, John P.

AU - Presland, Richard B.

AU - Fleckman, Philip

AU - Shimizu, Nobuyoshi

AU - Kudoh, Jun

AU - Irvine, Alan D.

AU - Amagai, Masayuki

AU - McLean, W. H. Irwin

PY - 2009/5

Y1 - 2009/5

N2 - Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris(1) and convey major genetic risk for atopic dermatitis (eczema)(2-4), eczema-associated asthma(2,3) and other allergic phenotypes(5). Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of similar to 9% in Europe(4). Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). 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 flaky tail 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.

AB - Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris(1) and convey major genetic risk for atopic dermatitis (eczema)(2-4), eczema-associated asthma(2,3) and other allergic phenotypes(5). Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of similar to 9% in Europe(4). Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). 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 flaky tail 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.

KW - OF-FUNCTION MUTATIONS

KW - ATOPIC-DERMATITIS

KW - ICHTHYOSIS VULGARIS

KW - FILAGGRIN MUTATIONS

KW - HUMAN PROFILAGGRIN

KW - MICE

KW - EXPRESSION

KW - DISEASE

KW - ASTHMA

KW - ECZEMA

UR - https://www.scopus.com/pages/publications/66749163178

U2 - 10.1038/ng.358

DO - 10.1038/ng.358

M3 - Letter

C2 - 19349982

SN - 1061-4036

VL - 41

SP - 602

EP - 608

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -