Research ArticleGenetics

Mutations in Fibrillin-1 Cause Congenital Scleroderma: Stiff Skin Syndrome

Science Translational Medicine  17 Mar 2010:
Vol. 2, Issue 23, pp. 23ra20
DOI: 10.1126/scitranslmed.3000488

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Variation in Rare Disease Linked to Common Skin Disorder

In the epic words of British physician and researcher Dr. William Harvey, “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature by the careful investigation of cases of rarer forms of disease. For it has been found in almost all things, that what they contain of useful or of applicable nature, is hardly perceived unless we are deprived of them, or they become deranged in some way.” Such is the case for rare genetic diseases, which have provided the framework to understand some of the most devastating common diseases from just the simple permutation of a gene.

Scleroderma, which literally means a pathological hardening of the skin, manifests as a complex phenotype. To better understand the etiology of scleroderma, Loeys and colleagues investigate four families with more than 10 affected individuals with a rare congenital form called stiff skin syndrome—which together account for more than 25% of the total cases currently documented in the literature—and identify the key mutations in a gene that encodes the connective tissue protein fibrillin-1. Fibrosis is not only seen in the context of systemic connective tissue disorders, but rather is often the major signature of the inflammatory burden in many common disorders, providing incentive to understand the factors critical in the initiation and maintenance of profibrotic programs. Mutations causing stiff skin syndrome cluster within a single domain of fibrillin-1 that mediates integin binding. Low amounts of an activated protein kinase that is triggered by ligand-integrin interactions provided further evidence for altered cell matrix interactions. This associates with evidence for activation of the TGFβ signaling cascade, a mechanism to instruct cells to deposit collagens and other matrix elements both during normal wound healing and in various fibrotic states. These data are consistent with a model in which integrins provide a means for cells to sample the matrix and to adjust their synthetic repertoire accordingly. Loss of this feedback would culminate in fibrosis. The results garnered from these patients with this rare disease prompted the authors to examine skin biopsies from five patients with common scleroderma, which surprisingly revealed that each scleroderma patient showed all of the abnormalities seen in stiff skin syndrome. These findings reinforce the power of studying rare genetic disorders to inform the underlying causes of common diseases, but also unveil a potential avenue for therapeutic intervention in common disorders that include fibrosis.


  • * These authors contributed equally to this work.

  • Citation: B. L. Loeys, E. E. Gerber, D. Riegert-Johnson, S. Iqbal, P. Whiteman, V. McConnell, C. R. Chillakuri, D. Macaya, P. J. Coucke, A. De Paepe, D. P. Judge, F. Wigley, E. C. Davis, H. J. Mardon, P. Handford, D. R. Keene, L. Y. Sakai, H. C. Dietz, Mutations in Fibrillin-1 Cause Congenital Scleroderma: Stiff Skin Syndrome. Sci. Transl. Med. 2, 23ra20 (2010).

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