Gina Kolata in The New York Times:
For families who have recently learned that a child has Marfan syndrome, Dr. Dietz’s discoveries and the clinical trial he designed have divided their world into before and after, dread and hope. Daniel Speck of Knoxville, Md., was given a diagnosis of Marfan six years ago, when he was 8, after his pediatrician noticed his spine was curved and suggested a test for scoliosis. It turned out that the curvature was caused by Marfan syndrome. “We were blindsided,” said his mother, Amy Speck. Daniel was furious when he couldn’t play basketball anymore. By then, Dr. Dietz and his colleagues had finally found the gene mutation that causes Marfan. It had been a slow and frustrating process: The sequencing machines now used to quickly map DNA had not been invented. Researchers had to sort through every gene in large regions of DNA shared by members of families in which someone had the syndrome. Yet when the researchers first found the mutation, in 1990, it seemed to lead to a dead end. The mutation was in fibrillin-1, a protein in connective tissue, suggesting that the tissue was falling apart because its molecular rivets did not work.
…About 10 years ago, he and his colleagues discovered the answer in another protein, T.G.F.-beta, short for transforming growth factor beta, which tells cells how to behave during development and is used in repairing wounds. The protein’s function depends on fibrillin-1, the very protein that is altered in Marfan syndrome. Normally, fibrillin-1 hooks T.G.F.-beta to connective tissue. But in someone with Marfan, the researchers discovered, the fibrillin-1 is defective, and the process goes awry. Instead of attaching to the connective tissue, T.G.F.-beta drifts away from it. Floating free in the bloodstream, it makes cells behave abnormally, leading to many of the problems caused by Marfan, including excessive growth of the aorta. In short, the rivet model was entirely wrong. “That,” Dr. Dietz said, “was one of the few ‘aha’ moments in my life.” He tested his theory in mice, giving them the mutated fibrillin-1 gene. Sure enough, levels of the T.G.F. protein were very high. The mice showed Marfan symptoms, including emphysema, weak skeletal muscles and a thickening of the mitral valve in the heart. He sought a way to block the function of T.G.F.-beta and found a widely used blood pressure drug, losartan, that did just that.