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.

Abstract

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.

• Authors: Takashi Sasaki, Aiko Shiohama, Akiharu Kubo, Hiroshi Kawasaki, Akemi Ishida-Yamamoto, Taketo Yamada, Takayuki Hachiya, Atsushi Shimizu, Hideyuki Okano, Jun Kudoh, Masayuki Amagai
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 132 Issue 5 Pg. 1111-1120.e4 (Nov 2013) ISSN: 1097-6825 [Electronic] United States
• PMID: 24060273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Chemical References

• Codon, Nonsense
• FLG protein, human
• Filaggrin Proteins
• Membrane Proteins
• Tmem79 protein, mouse

Topics

• Animals
• Codon, Nonsense
• Dermatitis, Atopic (genetics, metabolism)
• Disease Models, Animal
• Eczema (genetics, metabolism)
• Epithelium (metabolism)
• Filaggrin Proteins
• Gene Expression
• Gene Order
• Homozygote
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Transgenic
• Phenotype
• Protein Transport
• Skin (metabolism, pathology)