Tenascin-X, collagen, elastin, and the Ehlers–Danlos syndrome

Authors

  • James Bristow,

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    • Joint Genome Institute, Walnut Creek, CA 94598.
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    • James Bristow is Deputy Director of the Department of Energy's Joint Genome Institute at Lawrence Berkeley National Laboratory and Professor of Pediatric Cardiology at the University of California, San Francisco. He was involved in the original cloning of tenascin-X and uses genetic approaches to understand the functions of tenascins in disease.

  • William Carey,

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    • William Carey is a neonatologist and Instructor in Pediatrics at the University of California, San Francisco. He is studying the role of tenascin-X and tenascin-C in pathologic fibrosis.

  • David Egging,

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    • David Egging is a molecular biologist at the Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre. He is studying the interactions of tenascin-X with extracellular matrix components.

  • Joost Schalkwijk

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    • Joost Schalkwijk is Professor of Experimental Dermatology at Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. His career has centered on understanding basic mechanisms of a variety of skin diseases and he developed essential methodology for studying the role of tenascin-X in Ehlers–Danlos syndrome.


Abstract

Tenascin-X is an extracellular matrix protein initially identified because the gene encoding it overlaps with the human CYP21B gene. Because studies of gene and protein function of other tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating tenascin-X mutations and novel recessive and dominant forms of Ehlers–Danlos syndrome (EDS). Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes EDS. Tenascin-X null mice recapitulate the skin findings of the human disease, confirming a causative role for this gene in EDS. Further evaluation of these mice showed that tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of EDS. Further studies suggest that tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human “experiments of nature” can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins. © 2005 Wiley-Liss, Inc.

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