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Study of Rare Genetic Disorder Suggests Role for Fibrillin-1 in Scleroderma

By studying the genetics of an autosomal dominant disorder called “stiff skin syndrome,” a rare congenital form of scleroderma, researchers at the Johns Hopkins University School of Medicine and collaborating institutions have learned more about the much more common acquired form of scleroderma, also called systemic sclerosis. Systemic sclerosis affects approximately one in 5,000 people and leads to hardening of the skin, as well as to other debilitating and often life-threatening problems. “[Acquired] scleroderma is a common and often devastating condition, yet its cause remains mysterious. My greatest hope is that this work will facilitate the development of new and better treatments,” said senior author Dr. Harry C Dietz, the Victor A. McKusick Professor of Genetics and Director of the Johns Hopkins William S. Smilow Center for Marfan Syndrome Research. Acquired scleroderma generally affects previously healthy young adults, causing scarring of skin and internal organs that can lead to heart and lung failure. “Most often individuals with [acquired] scleroderma do not have other affected family members, precluding use of genetic techniques to map the underlying genes. Instead, we turned to a rare but inherited form of isolated skin fibrosis called “stiff skin syndrome,” hoping to gain a foothold regarding cellular mechanisms that might prove relevant to both conditions,” said Dr. Dietz. A number of clues led Dr. Dietz and his team to strongly suspect a role for the connective tissue protein fibrillin-1 in these skin conditions. First, excess collagen is a hallmark feature of both stiff skin syndrome and acquired scleroderma. While studying Marfan syndrome, an inherited connective tissue condition caused by a deficiency of fibrillin-1, the researchers discovered that fibrillin-1 regulates the activity of TGF-beta, a molecule that induces cells to make more collagen. Second, other researchers have shown that duplication of a segment within the fibrillin-1 gene is associated with skin fibrosis in mice. And third, Dr. Dietz treated a patient at Johns Hopkins who had both stiff skin syndrome and eye problems associated with Marfan syndrome. “This seemed too much of a coincidence,” he said.

So Dr. Dietz’s team examined patients with stiff skin syndrome and found them to have excessive amounts of fibrillin-1 in the skin. The researchers then sequenced the fibrillin-1 gene in these same patients and found all the stiff skin syndrome mutations clustered in a single region of the fibrillin-1 protein known to interact with neighboring cells. Further examination showed that these mutations prevent fibrillin-1 from interacting with neighboring cells and lead to increased amounts and activity of TGF-beta, which causes excessive collagen to accumulate outside cells.

The researchers then examined biopsies from patients with acquired scleroderma and found all of the abnormalities seen in stiff skin syndrome. “It appears that fibriillin-1 helps to inform cells about the quality of their surroundings and also provides a mechanism--by concentrating TGF-beta--to induce extra cellular matrix production if the cell senses a deficiency,” said Dr. Dietz. “A breakdown in signaling coupled with excessive fibrillin-1 and TGF-beta leads to a perfect storm for skin fibrosis in stiff skin syndrome.”

While it remains unknown what triggers similar molecular events in acquired scleroderma, the current findings do suggest a number of potential treatment strategies, said Dr. Dietz.

This research was published in the March 17, 2010 issue of Science Translational Medicine. [Press release] [Science Translational Medicine abstract]