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| |  Researchers Have New Tool For Understanding Marfan Syndrome WASHINGTON, MD. – September 30, 1997 -- Scientists have for the first time created mice with a genetic condition that resembles Marfan syndrome, a potentially-fatal hereditary connective tissue disorder that weakens tissues of the skeleton, eyes, lungs, heart and blood vessels. Analyses of the mice provide an unexpected new view of the connective tissue defects, especially aortic aneurysms, that occur in people with Marfan syndrome. The mice will serve as a valuable animal model for understanding human disease and developing new treatments, and may lead to insights on aortic aneurysms in general. Marfan syndrome, which affects about one in every 5,000 people, is perhaps best known for causing the sudden deaths of Olympic volleyball star Flo Hyman and University of Maryland basketball player Chris Patton. Neither of these athletes were diagnosed as having the disorder until after their deaths from ruptured aortic aneurysms. An aortic aneurysm is a weak spot in the aorta -- the main artery that carries oxygen-rich blood from the heart to the rest of the body. These weak spots can tear or rupture under stress. Aortic aneurysms account for about two percent of all deaths in industrialized countries and are a leading cause of death in people with Marfan syndrome. If the disorder is diagnosed in time, doctors can take steps to reduce the risk of aortic rupture. But the symptoms and severity of Marfan syndrome vary quite widely and many cases go undiagnosed. Scientists have speculated Abraham Lincoln had Marfan syndrome, because of his tall, lanky stature and long fingers. In their research on Marfan syndrome, Dr. Francesco Ramirez and Dr. Lygia Pereira of Mount Sinai School of Medicine in New York, Dr. Lynn Y. Sakai of Shriners Hospital for Children in Portland, OR., Dr. Harry C. Dietz of Johns Hopkins University in Baltimore, MD. and their colleagues created and studied mice with a mutation in the gene for a protein called fibrillin-1. The fibrillin-1 gene is known to be mutated in people with Marfan syndrome. The researchers found mice with two copies of the mutant fibrillin-1gene all died suddenly and prematurely of cardiovascular complications. The majority of mice examined after death had evidence of aortic aneurysms or other signs of weakened blood vessels. Tissues from the mice had substantially reduced levels of fibrillin-1 protein. Fibrillin-1 is found in tissues that are rich in so-called elastic fibers, such as the skin, lungs, ligaments and blood vessel walls. Like spandex fibers woven into clothing, elastic fibers let these tissues stretch without tearing. In the early 1990s, researchers discovered Marfan syndrome is caused by a variety of mutations in the fibrillin-1 gene. These mutations are thought to disrupt development of elastic fibers in connective tissues throughout the body, causing people with the disorder to have long, thin limbs and especially long fingers; a curved spine; eye problems due to weakness of the ligaments holding the lens in place; and cardiovascular problems including leaky heart valves as well as aortic aneurysms. The main component of elastic fibers is a protein called elastin, which forms the core of the mature fiber. The elastin core is covered by a sheath of fibers (called microfibrils) made up of fibrillin-1 and other proteins. Microfibrils are believed to play an important role in the early stages of elastic fiber development, acting as a scaffold onto which elastin molecules are deposited. As the elastic fiber grows and matures, the microfibrils move to the outside, forming a wrapping around the elastin core. The mutant mice created by Ramirez and colleagues had sharply reduced levels of fibrillin-1 microfibrils, which the researchers predicted would impair formation of the normal elastic fiber network in tissues such as skin and blood vessels. To their surprise, the researchers found elastin-containing elastic fiber networks still formed in connective tissues from these mice and these fibers appeared normal when examined under a microscope. The results indicate that, unlike what was thought before, the progression of Marfan syndrome is not due to failure of formation of an elastic fiber network, but is because the network that forms is defective, Ramirez explained. He predicts a second fibrillin gene, fibrillin-2, or perhaps several genes, play an important role in elastic fiber development and fibrillin-1 is just one of several proteins that form the scaffolding for elastin in developing elastic fibers. Ramirez said these findings have implications for the possible future design of gene therapy for Marfan syndrome. In addition, he says, he and his colleagues hope to expand their studies to genetically engineer mice that live longer and will allow us to study the development and progress of aortic aneurysms in general, as well as in Marfan syndrome, and see if we can develop therapies that allow us to prevent them. The research, reported in the October 1997 issue of Nature Genetics, was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health; the National Marfan Foundation; and several other organizations.
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