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 Kudo, Masayuki Amagai

Research output: Contribution to journalArticle

62 Citations (Scopus)

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
JournalJournal of Allergy and Clinical Immunology
Volume132
Issue number5
DOIs
Publication statusPublished - 2013 Nov

Fingerprint

Nonsense Codon
Eczema
Secretory Vesicles
Atopic Dermatitis
Theoretical Models
Dermatitis
Genes
Phenotype
Mutation
Hair
Cornea
Tail
trans-Golgi Network
Specific Pathogen-Free Organisms
Frameshift Mutation
Inbreeding
Granulosa Cells
Transgenes
DNA Sequence Analysis
Epidermis

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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

In: Journal of Allergy and Clinical Immunology, Vol. 132, No. 5, 11.2013.

Research output: Contribution to journalArticle

@article{41943ca92ace421591c5a6a5544e960b,
title = "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 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.",
keywords = "Atopic dermatitis, filaggrin, skin barrier, stratum corneum, trans-Golgi network",
author = "Takashi Sasaki and Aiko Shiohama and Akiharu Kubo and Hiroshi Kawasaki and Akemi Ishida-Yamamoto and Taketo Yamada and Takayuki Hachiya and Atsushi Shimizu and Hideyuki Okano and Jun Kudo and Masayuki Amagai",
year = "2013",
month = "11",
doi = "10.1016/j.jaci.2013.08.027",
language = "English",
volume = "132",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "5",

}

TY - JOUR

T1 - 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

AU - Sasaki, Takashi

AU - Shiohama, Aiko

AU - Kubo, Akiharu

AU - Kawasaki, Hiroshi

AU - Ishida-Yamamoto, Akemi

AU - Yamada, Taketo

AU - Hachiya, Takayuki

AU - Shimizu, Atsushi

AU - Okano, Hideyuki

AU - Kudo, Jun

AU - Amagai, Masayuki

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

KW - Atopic dermatitis

KW - filaggrin

KW - skin barrier

KW - stratum corneum

KW - trans-Golgi network

UR - http://www.scopus.com/inward/record.url?scp=84887025956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887025956&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2013.08.027

DO - 10.1016/j.jaci.2013.08.027

M3 - Article

C2 - 24060273

AN - SCOPUS:84887025956

VL - 132

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 5

ER -