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

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 5; pp. 1111 - 1120.e4
• Main Authors: Sasaki, Takashi, PhD, Shiohama, Aiko, PhD, Kubo, Akiharu, MD, PhD, Kawasaki, Hiroshi, MD, PhD, Ishida-Yamamoto, Akemi, MD, PhD, Yamada, Taketo, MD, PhD, Hachiya, Takayuki, PhD, Shimizu, Atsushi, PhD, Okano, Hideyuki, MD, PhD, Kudoh, Jun, PhD, Amagai, Masayuki, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.11.2013; Elsevier; Elsevier Limited
• Subjects: Allergic diseases; Allergy and Immunology; Animals; Artificial chromosomes; Atopic dermatitis; Biological and medical sciences; Codon, Nonsense; Deoxyribonucleic acid; Dermatitis, Atopic - genetics; Dermatitis, Atopic - metabolism; Disease Models, Animal; DNA; Eczema - genetics; Eczema - metabolism; Epithelium - metabolism; filaggrin; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression; Gene Order; Genomes; Genomics; Genotype & phenotype; Homozygote; Hydration; Immunopathology; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Microscopy; Mutation; Phenotype; Protein Transport; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sheep; Skin - metabolism; Skin - pathology; Skin allergic diseases. Stinging insect allergies; skin barrier; Software; stratum corneum; trans-Golgi network; Japan; Flg; Corneodesmosin; SPF; SC; stratum corneum; Specific pathogen free; ma; SG; Single nucleotide variation; Atopic dermatitis; SNV; filaggrin; WT; skin barrier; Matted; TEWL; AD; CDSN; Stratum granulosum; Transepidermal water loss; Wild type; trans-Golgi network; Lamellar granule; TGN; LG; Allergy; Immunopathology; Skin disease; Stratum corneum; Nonsense mutation; Spontaneous; Filaggrin; Experimental study; Homozygosity; Atopy; Golgi apparatus; Immunology; Gene; Eczema; Network; Genetics; Models; Skin; Trans-Golgi network
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.08.027

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.