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

Nature Genetics volume 30, pages 421–425 (2002)Cite this article

Abstract

Tenascin-X is a large extracellular matrix protein of unknown function1,2,3. Tenascin-X deficiency in humans is associated with Ehlers–Danlos syndrome4,5, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens6. Because TNXB is the first Ehlers–Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme7,8,9,10,11,12,13,14, we suggested that tenascin-X might regulate collagen synthesis or deposition15. 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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Figure 1: Gene targeting of Tnxb.
Figure 2: Skin phenotype of Tnxb−/− mice.
Figure 3: Biomechanical testing of skin.
Figure 4: Analysis of collagen in skin.
Figure 5: Tnxb facilitates collagen deposition.

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Acknowledgements

This work was supported by grants to J. Bristow from the National Institutes of Health and the March of Dimes Birth Defects Foundation. We would like to thank T. Huby for assistance with ES cell culture, P. Byers for encouragement and advice on the metabolic labeling experiments, and L. Pennacchio for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, University of California, Laurel Heights Campus, 3333 California Street, Box 1245, San Francisco, 94118, California, USA

    Jau Ren Mao, Glen Taylor, Willow B. Dean & James Bristow

  2. Department of Orthopedic Surgery, University of California, Laurel Heights Campus, 3333 California Street, Box 1245, San Francisco, 94118, California, USA

    Diane R. Wagner & Jeffrey C. Lotz

  3. Genome Sciences, Lawrence Berkeley National Laboratory, Berkeley, California, USA

    Willow B. Dean, Veena Afzal, Edward M. Rubin & James Bristow

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Correspondence to James Bristow.

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Mao, J., Taylor, G., Dean, W. et al. Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition. Nat Genet 30, 421–425 (2002). https://doi.org/10.1038/ng850

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