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Sci Transl Med. 2010 Mar 17;2(23):23ra20. doi: 10.1126/scitranslmed.3000488.

Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome.

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1
Institute of Genetic Medicine and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Broadway Research Building, Room 539, 733 North Broadway, Baltimore, MD 21205, USA.

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-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta 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.

PMID:
20375004
PMCID:
PMC2953713
DOI:
10.1126/scitranslmed.3000488
[Indexed for MEDLINE]
Free PMC Article
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