A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:132

Article

Sasaki, Takashi^1,5  Shiohama, Aiko^6,7  Kubo, Akiharu^1,5  Kawasaki, Hiroshi¹  Ishida-Yamamoto, Akemi⁸  Yamada, Taketo²  Hachiya, Takayuki⁹  Shimizu, Atsushi³  Okano, Hideyuki⁴  Kudoh, Jun⁷  Amagai, Masayuki^1,6 

[1] Keio Univ, Sch Med, Dept Dermatol, Tokyo, Japan

[2] Keio Univ, Sch Med, Dept Pathol, Tokyo 160, Japan

[3] Keio Univ, Sch Med, Dept Mol Biol, Tokyo, Japan

[4] Keio Univ, Sch Med, Dept Physiol, Tokyo 160, Japan

[5] Keio Univ, Sch Med, Ctr Integrated Med Res, Tokyo, Japan

[6] Keio Univ, Sch Med, MSD Endowed Program Allergy Res, Tokyo, Japan

[7] Keio Univ, Sch Med, Lab Gene Med, Tokyo, Japan

[8] Asahikawa Med Univ, Dept Dermatol, Asahikawa, Hokkaido, Japan

[9] Med & Biol Labs Co Ltd, Nagano, Japan

关键词: Atopic dermatitis;    skin barrier;    stratum corneum;    trans-Golgi network;    filaggrin;   

DOI  :  10.1016/j.jaci.2013.08.027

来源: Elsevier

【 摘 要 】

Background: Flaky tail (ma/ma Flg(ft/ft)) mice have a frameshift mutation in the filaggrin (Flg(ft)) gene and are widely used as a model of human atopic dermatitis associated with FLG mutations. These mice possess another recessive hair mutation, matted (ma), and develop spontaneous dermatitis under specific pathogen-free conditions, whereas genetically engineered Flg(-/-) mice do not. Objective: We identified and characterized the gene responsible for the matted hair and dermatitis phenotype in flaky tail mice. Methods: We narrowed down the responsible region by backcrossing ma/ma mice with wild-type mice and identified the mutation using next-generation DNA sequencing. We attempted to rescue the matted phenotype by introducing the wild-type matted transgene. We characterized the responsible gene product by using whole-mount immunostaining of epidermal sheets. Results: We demonstrated that ma, but not Flg(ft), was responsible for the dermatitis phenotype and corresponded to a Tmem79 gene nonsense mutation (c.840C>G, p.Y280*), which encoded a 5-transmembrane protein. Exogenous Tmem79 expression rescued the matted hair and dermatitis phenotype of Tmem79(ma/ma) mice. Tmem79 was mainly expressed in the trans-Golgi network in stratum granulosum cells in the epidermis in both mice and humans. The Tmem79(ma/ma) mutation impaired the lamellar granule secretory system, which resulted in altered stratum corneum formation and a subsequent spontaneous dermatitis phenotype. Conclusions: The Tmem79(ma/ma) mutation is responsible for the spontaneous dermatitis phenotype in matted mice, probably as a result of impaired lamellar granule secretory system and altered stratum corneum barrier function.

【 授权许可】

Free