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.
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.
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Center for Integrated Medical Research, Keio University School of Medicine, Tokyo, Japan.
Takashi
T
Sasaki
Aiko
A
Shiohama
Akiharu
A
Kubo
Hiroshi
H
Kawasaki
Akemi
A
Ishida-Yamamoto
Taketo
T
Yamada
Takayuki
T
Hachiya
Atsushi
A
Shimizu
Hideyuki
H
Okano
Jun
J
Kudoh
Masayuki
M
Amagai
D000818:Animals; D018389:Codon, Nonsense; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004485:Eczema / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D000091344:Filaggrin Proteins; D015870:Gene Expression; D023061:Gene Order; D006720:Homozygote; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D021381:Protein Transport; D012867:Skin / Q000378:metabolism / Q000473:pathology
D018389:Codon, Nonsense; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D008565:Membrane Proteins; C585425:Tmem79 protein, mouse
AD; Atopic dermatitis; CDSN; Corneodesmosin; Filaggrin; Flg; LG; Lamellar granule; Matted; SC; SG; SNV; SPF; Single nucleotide variation; Specific pathogen free; Stratum corneum; Stratum granulosum; TEWL; TGN; Trans-Golgi network; Transepidermal water loss; WT; Wild type; filaggrin; ma; skin barrier; stratum corneum; trans-Golgi network