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Cited by 261Connective tissue disorders researchSkin and Cellular Biology ResearchDermatological and Skeletal Disorders

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Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition

Mao, Jau Ren, Taylor, Glen, Dean, Willow B., Wagner, Diane R., Afzal, Veena, Lotz, Jeffrey C., Rubin, Edward M., Bristow, James·2002·Nature Genetics
DOI 10.1038/ng850
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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.

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Research works printed but not linked: 26

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Metadata

Authors
Mao, J. R., Taylor, G., Dean, W. B., Wagner, D. R., Afzal, V., Lotz, J. C., Rubin, E. M., & Bristow, J.
Affiliations
  • University of California, San Francisco (US)
  • Lawrence Berkeley National Laboratory (US)
Corresponding author
Bristow, James
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2002-03-04
Volume
30
Issue
4
Pages
421-425
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng850
OpenAlex
W2062321035
Cited by
261
References
0
Citations by year
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FWCI
7.43
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
Keywords
tenascin-X, TNXB, Ehlers-Danlos syndrome, collagen deposition, type I collagen, dermal fibroblasts, skin hyperextensibility, connective tissue diseases, extracellular matrix, skin biomechanics, knockout mice
MeSH terms
Animals, Collagen, Ehlers-Danlos Syndrome, Exons, Fibroblasts, Humans, Male, Microscopy, Electron, Microscopy, Fluorescence, Models, Genetic, Molecular Sequence Data, Mutation, Phenotype, Plasmids, Recombination, Genetic, Skin Physiological Phenomena, Time Factors, Immunoblotting, Mice, Knockout, Tenascin, Mice

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