The discovery by School of Medicine researchers of a mutated gene associated with a rare skin disorder should give insight into more common diseases such as emphysema and aortic aneurysms.
Zsolt Urban, Ph.D., assistant professor of pediatrics and of genetics in the School of Medicine, and his fellow researchers discovered that a mutated gene, fibulin-4, causes a novel form of recessive cutis laxa, a disorder that results in severe connective tissue abnormalities in affected children.
The research is available online and will be published in the June issue of the American Journal of Human Genetics.
Cutis laxa, a genetic dermatologic condition, is characterized by unusually loose skin that may hang in folds off of the body due to underdeveloped elastic fibers. The research also found that mutations in fibulin-4 cause fragile bones, twisted blood vessels, aortic aneurysm, developmental emphysema and hernia in the diaphragm and groin areas.
Fibulins are a newly recognized group of matrix proteins that interact with other matrix proteins outside of cells, including elastic fibers. Urban’s research is the first to associate fibulin-4 with recessive cutis laxa syndrome.
Urban and his fellow researchers discovered the mutated fibulin-4 gene in a 2-year-old child who had inherited a recessive, mutated fibulin-4 gene from each parent. She was born with cutis laxa and multiple bone fractures and developed an aortic aneurysm, emphysema, hernia and lax joints.
“These clinical observations show that fibulin-4 is important for a variety of connective tissues,” Urban said. “A defect in any of the molecules necessary for elastic fiber formation could result in disease, such as cutis laxa.”
Urban plans to use the findings to manipulate the fibulin-4 gene in zebrafish to create a research model for studying recessive cutis laxa. The transparency of the developing zebrafish will allow the researchers to observe the role of fibulin-4 in causing cutis laxa in a zebrafish embryo.
“It’s possible that there is an early developmental dysfunction that causes cutis laxa,” Urban said. “In the zebrafish, we can see where the gene is activated, inactivate it and create a similar phenotype to what we have observed in the patient.”
There are no drugs to treat cutis laxa and no known preventive measures. The recessive form of cutis laxa is fatal because of the emphysema and the aortic aneurysms, which could lead to sudden death if they rupture.
The only way to treat the disease is through cosmetic surgeries to repair the skin, although those often need to be repeated because of the continued laxness of the skin. Patients require a lung transplant in cases of severe emphysema and surgical repair of an aortic aneurysm.
“Once we recreate the disease in zebrafish, we can look for drugs that might be beneficial to patients with this disorder and more common diseases like emphysema and then screen those drugs on the zebrafish,” Urban said.
Urban has established an International Center for the Study of Cutis Laxa at St. Louis Children’s Hospital, where a multi-disciplinary team treats patients and investigates additional genetic causes of this disorder. Other School of Medicine faculty involved in the center include Susan Bayliss Mallory, M.D., professor of pediatrics and of dermatology; Kathy Grange, M.D., and Michael R. DeBaun, M.D., both associate professors of pediatrics and experts in human genetics; and Mark C. Johnson, M.D., associate professor of pediatrics and an expert in cardiology.
“Zsolt’s tremendous new findings are a wonderful example of the value in exploring the genetic mechanisms of rare diseases,” said Jonathan Gitlin, M.D., the Helene B. Roberson Professor of Pediatrics and director of the Division of Genetics and Genomic Medicine at Children’s Hospital. “Indeed, his work has great potential to provide insight into the causes of more common cardiovascular diseases in children.”