The discovery by researchers at Washington University School of Medicine in St. Louis of a mutated gene associated with a rare skin disorder should provide insight into more common diseases such as emphysema and aortic aneurysms.
Zsolt Urban, Ph.D., assistant professor of pediatrics and of genetics at the School of Medicine, fellow researchers Katherine Kim and Brad Angle at the Children’s Memorial Hospital in Chicago and Lihua Mamorstein at the University of Arizona, 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 appear 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 hernias 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 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 says. “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 says. “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.”
Currently, 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 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,” says Urban.
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 expert in cardiology.
“Zsolt’s tremendous new findings are a wonderful example of the value in exploring the genetic mechanisms of rare diseases,” says Jonathan Gitlin, M.D., the Helene B. Roberson Professor of Pediatrics and Director of the Division of Genetics and Genomic Medicine at St. Louis Children’s Hospital. “Indeed, his work has great potential to provide insight into the causes of more common cardiovascular diseases in children. His innovative approach to then study disease mechanisms and therapeutics in the zebrafish is another example of the power of this model system to help us understand childhood disease.
“Using the Pediatric Zebrafish program, he will be able to go from the bedside to the bench and back again to offer new hope to affected children and their families,” Gitlin said. “This is the mission of the Genetics and Genomic Medicine Division.”
Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
This research was funded by a grant from the National Institutes of Health.
Hucthagowder V., Sausgruber N., Kim K., Angle B., Marmorstein L., Urban Z. Fibulin-4: A novel gene for an autosomal recessive cutis laxa syndrome. The American Journal of Human Genetics Volume 79 June 2006.