Mutations in fibrillin-1 cause congenital scleroderma: Stiff skin syndrome

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

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Abstract

The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-β (TGFβ). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFβ concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.

Original languageEnglish (US)
Pages (from-to)23ra20
JournalScience translational medicine
Volume2
Issue number23
DOIs
StatePublished - Jun 7 2010

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ASJC Scopus subject areas

  • Medicine(all)

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Loeys, B. L., Gerber, E. E., Riegert-Johnson, D., Iqbal, S., Whiteman, P., McConnell, V., Chillakuri, C. R., Macaya, D., Coucke, P. J., Paepe, A. D., Judge, D. P., Wigley, F., Davis, E. C., Mardon, H. J., Handford, P., Keene, D. R., Sakai, L. Y., & Dietz, H. C. (2010). Mutations in fibrillin-1 cause congenital scleroderma: Stiff skin syndrome. Science translational medicine, 2(23), 23ra20. https://doi.org/10.1126/scitranslmed.3000488