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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 unde...

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Published in:Journal of allergy and clinical immunology 2013-11, Vol.132 (5), p.1111-1120.e4
Main Authors: Sasaki, Takashi, PhD, Shiohama, Aiko, PhD, Kubo, Akiharu, MD, PhD, Kawasaki, Hiroshi, MD, PhD, Ishida-Yamamoto, Akemi, MD, PhD, Yamada, Taketo, MD, PhD, Hachiya, Takayuki, PhD, Shimizu, Atsushi, PhD, Okano, Hideyuki, MD, PhD, Kudoh, Jun, PhD, Amagai, Masayuki, MD, PhD
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cited_by cdi_FETCH-LOGICAL-c579t-5b455b714b58ab7befdef691e1cf0bb2b92fccb5625931442b7beef9b22ac95c3
cites cdi_FETCH-LOGICAL-c579t-5b455b714b58ab7befdef691e1cf0bb2b92fccb5625931442b7beef9b22ac95c3
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container_title Journal of allergy and clinical immunology
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creator Sasaki, Takashi, PhD
Shiohama, Aiko, PhD
Kubo, Akiharu, MD, PhD
Kawasaki, Hiroshi, MD, PhD
Ishida-Yamamoto, Akemi, MD, PhD
Yamada, Taketo, MD, PhD
Hachiya, Takayuki, PhD
Shimizu, Atsushi, PhD
Okano, Hideyuki, MD, PhD
Kudoh, Jun, PhD
Amagai, Masayuki, MD, PhD
description 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.
doi_str_mv 10.1016/j.jaci.2013.08.027
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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&gt;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.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2013.08.027</identifier><identifier>PMID: 24060273</identifier><identifier>CODEN: JACIBY</identifier><language>eng</language><publisher>New York, NY: Mosby, Inc</publisher><subject>Allergic diseases ; Allergy and Immunology ; Animals ; Artificial chromosomes ; Atopic dermatitis ; Biological and medical sciences ; Codon, Nonsense ; Deoxyribonucleic acid ; Dermatitis, Atopic - genetics ; Dermatitis, Atopic - metabolism ; Disease Models, Animal ; DNA ; Eczema - genetics ; Eczema - metabolism ; Epithelium - metabolism ; filaggrin ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Gene Expression ; Gene Order ; Genomes ; Genomics ; Genotype &amp; phenotype ; Homozygote ; Hydration ; Immunopathology ; Medical sciences ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mice, Transgenic ; Microscopy ; Mutation ; Phenotype ; Protein Transport ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Sheep ; Skin - metabolism ; Skin - pathology ; Skin allergic diseases. Stinging insect allergies ; skin barrier ; Software ; stratum corneum ; trans-Golgi network</subject><ispartof>Journal of allergy and clinical immunology, 2013-11, Vol.132 (5), p.1111-1120.e4</ispartof><rights>American Academy of Allergy, Asthma &amp; Immunology</rights><rights>2013 American Academy of Allergy, Asthma &amp; Immunology</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2013 American Academy of Allergy, Asthma &amp; Immunology. Published by Mosby, Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Nov 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-5b455b714b58ab7befdef691e1cf0bb2b92fccb5625931442b7beef9b22ac95c3</citedby><cites>FETCH-LOGICAL-c579t-5b455b714b58ab7befdef691e1cf0bb2b92fccb5625931442b7beef9b22ac95c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=27933189$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24060273$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sasaki, Takashi, PhD</creatorcontrib><creatorcontrib>Shiohama, Aiko, PhD</creatorcontrib><creatorcontrib>Kubo, Akiharu, MD, PhD</creatorcontrib><creatorcontrib>Kawasaki, Hiroshi, MD, PhD</creatorcontrib><creatorcontrib>Ishida-Yamamoto, Akemi, MD, PhD</creatorcontrib><creatorcontrib>Yamada, Taketo, MD, PhD</creatorcontrib><creatorcontrib>Hachiya, Takayuki, PhD</creatorcontrib><creatorcontrib>Shimizu, Atsushi, PhD</creatorcontrib><creatorcontrib>Okano, Hideyuki, MD, PhD</creatorcontrib><creatorcontrib>Kudoh, Jun, PhD</creatorcontrib><creatorcontrib>Amagai, Masayuki, MD, PhD</creatorcontrib><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</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>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&gt;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.</description><subject>Allergic diseases</subject><subject>Allergy and Immunology</subject><subject>Animals</subject><subject>Artificial chromosomes</subject><subject>Atopic dermatitis</subject><subject>Biological and medical sciences</subject><subject>Codon, Nonsense</subject><subject>Deoxyribonucleic acid</subject><subject>Dermatitis, Atopic - genetics</subject><subject>Dermatitis, Atopic - metabolism</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>Eczema - genetics</subject><subject>Eczema - metabolism</subject><subject>Epithelium - metabolism</subject><subject>filaggrin</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Gene Expression</subject><subject>Gene Order</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype &amp; phenotype</subject><subject>Homozygote</subject><subject>Hydration</subject><subject>Immunopathology</subject><subject>Medical sciences</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy</subject><subject>Mutation</subject><subject>Phenotype</subject><subject>Protein Transport</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Sheep</subject><subject>Skin - metabolism</subject><subject>Skin - pathology</subject><subject>Skin allergic diseases. Stinging insect allergies</subject><subject>skin barrier</subject><subject>Software</subject><subject>stratum corneum</subject><subject>trans-Golgi network</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9kt1qVDEUhYModjr6Al5IQAQvOmOS8xsQoRT_oOCF9TokOftMM54kY5IjTp-sj2fSGS30QgiEkG_tvXZWEHpByZoS2r7drrdSmzUjtFqTfk1Y9wgtKOHdqu1Z8xgtCOF01XY1P0GnMW5JPlc9f4pOWE3ajFcLdHuOr731N_uNnyN23kXIC9s5yWS8w8bhdA14Aw7w6AO-smA7js-wxNrbnXfg0t1FoSZpYZpkwJsg3TwBjqADJB_2OO5jAnuGd8EPs4aIY9Ym6aC0BX0DVpZe0mH4vYNgbK4rJ2z9ABP2I5bJ74zGAwSbjSUTn6Eno5wiPD_uS_T944eri8-ry6-fvlycX6500_G0alTdNKqjtWp6qToF4wBjyylQPRKlmOJs1Fo1LWt4ReuaFQZGrhiTmje6WqI3h7rZ-c8ZYhLWRF3GvPMusqZnjPWMZ_TVA3Tr5-CyO0EbUvc1ZW2fKXagdPAxBhjFLo8rw15QIkquYitKrqLkKkgvSlBL9PJYelYWhn-Sv0Fm4PURkFHLacwBaBPvuY5XFe2Lx3cHDvKb_TIQRNQGnIbBBNBJDN7838f7B3I9GWdyxx-wh3g_r4hMEPGt_MDyAWmVi9SUV38AxZHZyA</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>Sasaki, Takashi, PhD</creator><creator>Shiohama, Aiko, PhD</creator><creator>Kubo, Akiharu, MD, PhD</creator><creator>Kawasaki, Hiroshi, MD, PhD</creator><creator>Ishida-Yamamoto, Akemi, MD, PhD</creator><creator>Yamada, Taketo, MD, PhD</creator><creator>Hachiya, Takayuki, PhD</creator><creator>Shimizu, Atsushi, PhD</creator><creator>Okano, Hideyuki, MD, PhD</creator><creator>Kudoh, Jun, PhD</creator><creator>Amagai, Masayuki, MD, PhD</creator><general>Mosby, Inc</general><general>Elsevier</general><general>Elsevier Limited</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20131101</creationdate><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</title><author>Sasaki, Takashi, PhD ; Shiohama, Aiko, PhD ; Kubo, Akiharu, MD, PhD ; Kawasaki, Hiroshi, MD, PhD ; Ishida-Yamamoto, Akemi, MD, PhD ; Yamada, Taketo, MD, PhD ; Hachiya, Takayuki, PhD ; Shimizu, Atsushi, PhD ; Okano, Hideyuki, MD, PhD ; Kudoh, Jun, PhD ; Amagai, Masayuki, MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c579t-5b455b714b58ab7befdef691e1cf0bb2b92fccb5625931442b7beef9b22ac95c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Allergic diseases</topic><topic>Allergy and Immunology</topic><topic>Animals</topic><topic>Artificial chromosomes</topic><topic>Atopic dermatitis</topic><topic>Biological and medical sciences</topic><topic>Codon, Nonsense</topic><topic>Deoxyribonucleic acid</topic><topic>Dermatitis, Atopic - genetics</topic><topic>Dermatitis, Atopic - metabolism</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>Eczema - genetics</topic><topic>Eczema - metabolism</topic><topic>Epithelium - metabolism</topic><topic>filaggrin</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Gene Expression</topic><topic>Gene Order</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotype &amp; phenotype</topic><topic>Homozygote</topic><topic>Hydration</topic><topic>Immunopathology</topic><topic>Medical sciences</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microscopy</topic><topic>Mutation</topic><topic>Phenotype</topic><topic>Protein Transport</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Sheep</topic><topic>Skin - metabolism</topic><topic>Skin - pathology</topic><topic>Skin allergic diseases. Stinging insect allergies</topic><topic>skin barrier</topic><topic>Software</topic><topic>stratum corneum</topic><topic>trans-Golgi network</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sasaki, Takashi, PhD</creatorcontrib><creatorcontrib>Shiohama, Aiko, PhD</creatorcontrib><creatorcontrib>Kubo, Akiharu, MD, PhD</creatorcontrib><creatorcontrib>Kawasaki, Hiroshi, MD, PhD</creatorcontrib><creatorcontrib>Ishida-Yamamoto, Akemi, MD, PhD</creatorcontrib><creatorcontrib>Yamada, Taketo, MD, PhD</creatorcontrib><creatorcontrib>Hachiya, Takayuki, PhD</creatorcontrib><creatorcontrib>Shimizu, Atsushi, PhD</creatorcontrib><creatorcontrib>Okano, Hideyuki, MD, PhD</creatorcontrib><creatorcontrib>Kudoh, Jun, PhD</creatorcontrib><creatorcontrib>Amagai, Masayuki, MD, PhD</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sasaki, Takashi, PhD</au><au>Shiohama, Aiko, PhD</au><au>Kubo, Akiharu, MD, PhD</au><au>Kawasaki, Hiroshi, MD, PhD</au><au>Ishida-Yamamoto, Akemi, MD, PhD</au><au>Yamada, Taketo, MD, PhD</au><au>Hachiya, Takayuki, PhD</au><au>Shimizu, Atsushi, PhD</au><au>Okano, Hideyuki, MD, PhD</au><au>Kudoh, Jun, PhD</au><au>Amagai, Masayuki, MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>132</volume><issue>5</issue><spage>1111</spage><epage>1120.e4</epage><pages>1111-1120.e4</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><coden>JACIBY</coden><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&gt;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.</abstract><cop>New York, NY</cop><pub>Mosby, Inc</pub><pmid>24060273</pmid><doi>10.1016/j.jaci.2013.08.027</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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subjects Allergic diseases
Allergy and Immunology
Animals
Artificial chromosomes
Atopic dermatitis
Biological and medical sciences
Codon, Nonsense
Deoxyribonucleic acid
Dermatitis, Atopic - genetics
Dermatitis, Atopic - metabolism
Disease Models, Animal
DNA
Eczema - genetics
Eczema - metabolism
Epithelium - metabolism
filaggrin
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Gene Expression
Gene Order
Genomes
Genomics
Genotype & phenotype
Homozygote
Hydration
Immunopathology
Medical sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Transgenic
Microscopy
Mutation
Phenotype
Protein Transport
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Sheep
Skin - metabolism
Skin - pathology
Skin allergic diseases. Stinging insect allergies
skin barrier
Software
stratum corneum
trans-Golgi network
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
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