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.
J Allergy Clin Immunol
; 132(5): 1111-1120.e4, 2013 Nov.
Article
em En
| MEDLINE
| ID: mdl-24060273
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.Palavras-chave
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
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Base de dados:
MEDLINE
Assunto principal:
Códon sem Sentido
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Dermatite Atópica
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Eczema
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Homozigoto
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Proteínas de Membrana
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article