Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition
Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome g...
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description | Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb−/− mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb−/− mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb−/− mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb−/− and wildtype cells was similar, Tnxb−/− fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts. |
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At the ultrastructural level, collagen fibrils of Tnxb−/− mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb−/− and wildtype cells was similar, Tnxb−/− fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/ng850</identifier><identifier>PMID: 11925569</identifier><identifier>CODEN: NGENEC</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Agriculture ; Animal Genetics and Genomics ; Animals ; BASIC BIOLOGICAL SCIENCES ; Biological and medical sciences ; Biomechanics ; Biomedical and Life Sciences ; Biomedicine ; Bone surgery ; Cancer Research ; Classical genetics, quantitative genetics, hybrids ; COLLAGEN ; Collagen - metabolism ; CONNECTIVE TISSUE ; DEPOSITION ; Diagnosis ; Ehlers-Danlos syndrome ; Ehlers-Danlos Syndrome - genetics ; Exons ; FIBROBLASTS ; Fibroblasts - metabolism ; Fundamental and applied biological sciences. 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Biological and molecular evolution ; Human Genetics ; Humans ; Hyperplasia ; HYPOTHESIS ; Immunoblotting ; letter ; Male ; METABOLISM ; MICE ; Mice, Knockout ; Microscopy, Electron ; Microscopy, Fluorescence ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Phenotype ; Physiological aspects ; Plasmids - metabolism ; Protein deficiency ; PROTEINS ; Recombination, Genetic ; Risk factors ; SHAPE ; Skin ; Skin Physiological Phenomena ; SYNTHESIS ; Tenascin - deficiency ; Tenascin - genetics ; TENSILE PROPERTIES ; TESTING ; Time Factors ; Vertebrata</subject><ispartof>Nature Genetics, 2002-04, Vol.30 (4), p.421-425</ispartof><rights>Springer Nature America, Inc. 2002</rights><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2002 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Apr 2002</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c605t-2e6ee11b859755f85418cc8702c22fbe31d2defd4aa9f9674dd7f1408e7c65513</citedby><cites>FETCH-LOGICAL-c605t-2e6ee11b859755f85418cc8702c22fbe31d2defd4aa9f9674dd7f1408e7c65513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,885,2727,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13590439$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11925569$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/821322$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Bristow, James</creatorcontrib><creatorcontrib>Mao, Jau Ren</creatorcontrib><creatorcontrib>Taylor, Glen</creatorcontrib><creatorcontrib>Dean, Willow B</creatorcontrib><creatorcontrib>Wagner, Diane R</creatorcontrib><creatorcontrib>Afzal, Veena</creatorcontrib><creatorcontrib>Lotz, Jeffrey C</creatorcontrib><creatorcontrib>Rubin, Edward M</creatorcontrib><creatorcontrib>Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)</creatorcontrib><title>Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition</title><title>Nature Genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb−/− mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb−/− mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb−/− mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb−/− and wildtype cells was similar, Tnxb−/− fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.</description><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biological and medical sciences</subject><subject>Biomechanics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bone surgery</subject><subject>Cancer Research</subject><subject>Classical genetics, quantitative genetics, hybrids</subject><subject>COLLAGEN</subject><subject>Collagen - metabolism</subject><subject>CONNECTIVE TISSUE</subject><subject>DEPOSITION</subject><subject>Diagnosis</subject><subject>Ehlers-Danlos syndrome</subject><subject>Ehlers-Danlos Syndrome - genetics</subject><subject>Exons</subject><subject>FIBROBLASTS</subject><subject>Fibroblasts - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Function</subject><subject>GENES</subject><subject>Genetic aspects</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>HYPOTHESIS</subject><subject>Immunoblotting</subject><subject>letter</subject><subject>Male</subject><subject>METABOLISM</subject><subject>MICE</subject><subject>Mice, Knockout</subject><subject>Microscopy, Electron</subject><subject>Microscopy, Fluorescence</subject><subject>Models, Genetic</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Phenotype</subject><subject>Physiological aspects</subject><subject>Plasmids - metabolism</subject><subject>Protein deficiency</subject><subject>PROTEINS</subject><subject>Recombination, Genetic</subject><subject>Risk factors</subject><subject>SHAPE</subject><subject>Skin</subject><subject>Skin Physiological Phenomena</subject><subject>SYNTHESIS</subject><subject>Tenascin - deficiency</subject><subject>Tenascin - genetics</subject><subject>TENSILE PROPERTIES</subject><subject>TESTING</subject><subject>Time Factors</subject><subject>Vertebrata</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0uFr1DAUAPAiiptzf4EgVVHxQ2de2jTpxzGnDgYDneK3kEtfexltciYp7P775ezhcUNU-iEl-eUl7-Vl2TGQEyCleG97wciD7BBYVRfAQTxM_6SGoiJlfZA9CeGGEKgqIh5nBwANZaxuDjO8RquCNrb4kbfYGW3Q6nU-mtHokJ8vB_Sh-KDs4EIe1rb1bsTc2AQ05nHp3dQvczVE9CoaZ3PX5doNg-rRpngrF8xm-mn2qFNDwOPteJR9-3h-ffa5uLz6dHF2elnomrBYUKwRARaCNZyxTrAKhNaCE6op7RZYQkvTJdtKqaZral61Le8gpYRc14xBeZS9mOO6EI1MaUXUS-2sRR2loFBSmszb2ay8-zlhiHI0QWO6s0U3BSk4rwmlUCX55q-SA-M1UPgnBFEREOXm7Jf34I2bvE0lkZTSlFBDeUKvZtSrAaWxnYte6U1EeZqiVBQIEUmd_EGlr8X0Ns6mt0zzexve7W1IJuJt7NUUgrz4-uX_7dX3fft6ttq7EDx2cuXNqPxaApGb1pS_WjO559vcp8WI7U5te3EXaJUaUg2dV1absHMla0hVNrtqh7Rke_S7It4_8dkMrYqTx9-R5tU761f8rA</recordid><startdate>20020401</startdate><enddate>20020401</enddate><creator>Bristow, James</creator><creator>Mao, Jau Ren</creator><creator>Taylor, Glen</creator><creator>Dean, Willow B</creator><creator>Wagner, Diane R</creator><creator>Afzal, Veena</creator><creator>Lotz, Jeffrey C</creator><creator>Rubin, Edward M</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20020401</creationdate><title>Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition</title><author>Bristow, James ; Mao, Jau Ren ; Taylor, Glen ; Dean, Willow B ; Wagner, Diane R ; Afzal, Veena ; Lotz, Jeffrey C ; Rubin, Edward M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c605t-2e6ee11b859755f85418cc8702c22fbe31d2defd4aa9f9674dd7f1408e7c65513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>Animals</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biological and medical sciences</topic><topic>Biomechanics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bone surgery</topic><topic>Cancer Research</topic><topic>Classical genetics, quantitative genetics, hybrids</topic><topic>COLLAGEN</topic><topic>Collagen - metabolism</topic><topic>CONNECTIVE TISSUE</topic><topic>DEPOSITION</topic><topic>Diagnosis</topic><topic>Ehlers-Danlos syndrome</topic><topic>Ehlers-Danlos Syndrome - genetics</topic><topic>Exons</topic><topic>FIBROBLASTS</topic><topic>Fibroblasts - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Function</topic><topic>GENES</topic><topic>Genetic aspects</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>HYPOTHESIS</topic><topic>Immunoblotting</topic><topic>letter</topic><topic>Male</topic><topic>METABOLISM</topic><topic>MICE</topic><topic>Mice, Knockout</topic><topic>Microscopy, Electron</topic><topic>Microscopy, Fluorescence</topic><topic>Models, Genetic</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Phenotype</topic><topic>Physiological aspects</topic><topic>Plasmids - metabolism</topic><topic>Protein deficiency</topic><topic>PROTEINS</topic><topic>Recombination, Genetic</topic><topic>Risk factors</topic><topic>SHAPE</topic><topic>Skin</topic><topic>Skin Physiological Phenomena</topic><topic>SYNTHESIS</topic><topic>Tenascin - deficiency</topic><topic>Tenascin - genetics</topic><topic>TENSILE PROPERTIES</topic><topic>TESTING</topic><topic>Time Factors</topic><topic>Vertebrata</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bristow, James</creatorcontrib><creatorcontrib>Mao, Jau Ren</creatorcontrib><creatorcontrib>Taylor, Glen</creatorcontrib><creatorcontrib>Dean, Willow B</creatorcontrib><creatorcontrib>Wagner, Diane R</creatorcontrib><creatorcontrib>Afzal, Veena</creatorcontrib><creatorcontrib>Lotz, Jeffrey C</creatorcontrib><creatorcontrib>Rubin, Edward M</creatorcontrib><creatorcontrib>Lawrence Berkeley National Lab. 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(LBNL), Berkeley, CA (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition</atitle><jtitle>Nature Genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2002-04-01</date><risdate>2002</risdate><volume>30</volume><issue>4</issue><spage>421</spage><epage>425</epage><pages>421-425</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><coden>NGENEC</coden><abstract>Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb−/− mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb−/− mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb−/− mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb−/− and wildtype cells was similar, Tnxb−/− fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>11925569</pmid><doi>10.1038/ng850</doi><tpages>5</tpages></addata></record> |
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subjects | Agriculture Animal Genetics and Genomics Animals BASIC BIOLOGICAL SCIENCES Biological and medical sciences Biomechanics Biomedical and Life Sciences Biomedicine Bone surgery Cancer Research Classical genetics, quantitative genetics, hybrids COLLAGEN Collagen - metabolism CONNECTIVE TISSUE DEPOSITION Diagnosis Ehlers-Danlos syndrome Ehlers-Danlos Syndrome - genetics Exons FIBROBLASTS Fibroblasts - metabolism Fundamental and applied biological sciences. Psychology Gene Function GENES Genetic aspects Genetics of eukaryotes. Biological and molecular evolution Human Genetics Humans Hyperplasia HYPOTHESIS Immunoblotting letter Male METABOLISM MICE Mice, Knockout Microscopy, Electron Microscopy, Fluorescence Models, Genetic Molecular Sequence Data Mutation Phenotype Physiological aspects Plasmids - metabolism Protein deficiency PROTEINS Recombination, Genetic Risk factors SHAPE Skin Skin Physiological Phenomena SYNTHESIS Tenascin - deficiency Tenascin - genetics TENSILE PROPERTIES TESTING Time Factors Vertebrata |
title | Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition |
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