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

Takashi Sasaki, Aiko Shiohama, Akiharu Kubo, Hiroshi Kawasaki, Akemi Ishida-Yamamoto, Taketo Yamada, Takayuki Hachiya, Atsushi Shimizu, Hideyuki Okano, Jun Kudoh, Masayuki Amagai

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Abstract

Background Flaky tail (ma/ma Flgft/ft) mice have a frameshift mutation in the filaggrin (Flgft) 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 Flgft, 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 Tmem79ma/ma mutation impaired the lamellar granule secretory system, which resulted in altered stratum corneum formation and a subsequent spontaneous dermatitis phenotype. Conclusions The Tmem79ma/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.

Original languageEnglish
Pages (from-to)1111-1120.e4
JournalJournal of Allergy and Clinical Immunology
Volume132
Issue number5
DOIs
Publication statusPublished - 2013 Nov

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Keywords

  • Atopic dermatitis
  • filaggrin
  • skin barrier
  • stratum corneum
  • trans-Golgi network

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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