The study of the genetics of a rare hereditary disease called hard skin syndrome, researchers at the Johns Hopkins Medicine have learned more about scleroderma, a disease that affects about 5,000 people which led to a hardening of the skin and other debilitating and often fatal problems. The findings, appearing this week in Science Translational Medicine, the doors open to experimenting with new treatments. “Scleroderma is a mystery still common and often devastating yet their cause. My greatest hope is that this work will facilitate the development of new treatments and better,” said Harry C. Dietz, MD, Victor A. McKusick Professor of Genetics and director of the Johns Hopkins Center, William S. Smilow Marfan Syndrome Research.
Also known as systemic sclerosis, scleroderma usually affects previously healthy young adults, causing scarring of the skin and internal organs that can cause heart and lung failure. “Often, people with scleroderma have no family members involved, excluding the use of genetic techniques for mapping genes of the base. Instead, he went to a rare hereditary skin fibrosis isolated syndrome called Die Hard , with the hope of getting into the cellular mechanisms that may be relevant to both conditions, “said Dietz.
A series of clues led Dietz and his team strongly suspected a role of connective tissue protein fibrillin-1 in these skin diseases. First, excess collagen is a characteristic of both the hard skin syndrome and scleroderma. While the study of Marfan syndrome, a disease caused by a deficiency of fibrillin-1, researchers have found that fibrillin-1 regulates the activity of TGFbeta, a molecule that induces cells to produce more collagen. Second, other researchers have shown that the duplication of a segment in the fibrillin-1 gene is associated with skin fibrosis in mice. And third, a patient Dietz of Johns Hopkins University, who had both the hard skin syndrome and eye problems associated with Marfan syndrome. “It seemed too coincidental,” he said.
Thus, the team examined Dietz syndrome patients skin hard and found excessive amounts of fibrillin-1 in the skin. The researchers then sequenced the gene for fibrillin-1 in the same patients and found that mutations of the hard skin syndrome grouped in a region of fibrillin-1 protein known to interact with neighboring cells. further examination showed that these mutations prevent the fibrillin-1 interact with neighboring cells and result in an increased amount and activity of TGFbeta, which causes excessive collagen outside the cell.
The researchers then examined biopsies of scleroderma patients and found abnormalities in all the hard skin syndrome. “It seems that fibriillin-1 allows cells to inform the quality of their environment and also provides a mechanism – focusing TGFbeta – to induce extracellular matrix production if the cell detects a failure,” said Dietz. “The failure of the excessive signaling, along with the fibrillin-1 and TGFbeta leads to a perfect storm of skin fibrosis in the hard skin syndrome.
Although still unknown what triggers similar molecular events in scleroderma, these findings suggest a number of possible treatment strategies, “said Dietz.
This study was funded by the Scleroderma Research Foundation, Howard Hughes Medical Institute Smilow Center for Marfan Syndrome Research, National Marfan Foundation, the National Institutes of Health and the Shriners Hospital for children.
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