马方综合症.docVIP

? Reviewing the entry on Marfans syndrome in my medical school–era edition of Harrisons Principles of Internal Medicine, circa 1980, reminded me anew of the transformative potential of molecular medicine. In describing this striking genetic disorder, the textbook stated that the pathogenesis of Marfans syndrome was unknown but classified it as a connective-tissue disorder, a type of disorder that may affect any one of the numerous steps in the biosynthesis and the metabolism of or the processes by which the macromolecules are physically organized and oriented to one another.1 Fast-forward two decades, and a scientific drama involving Marfans syndrome and related disorders is playing out. The promise of translational research is being realized with improved diagnostics and prognostication, as well as the implementation of new therapeutic approaches that are informed by an understanding of the fundamental mechanisms of disease.????The first major breakthrough came in 1991, when missense mutations in the fibrillin-1 gene (FBN1) were discovered in two unrelated patients with Marfans syndrome.2 This finding was the culmination of biochemical studies that had identified fibrillin as an extracellular-matrix protein, specifically, a major component of microfibrils associated with elastin fibers. The research documented the presence of a fibrillin deficiency in patients with Marfans syndrome. Formal proof came from genetic investigations linking the trait to the region of chromosome 15 that was shown to contain FBN1, which in patients with Marfans syndrome harbored mutations.????Although exciting, these events left intact the basic paradigm of disease: that FBN1 mutations resulted in the production of abnormal fibrillin protein that, when incorporated into microfibrils along with normal fibrillin, resulted in structurally inferior connective tissue. This adverse effect of mutant proteins on normal ones, which geneticists term dominant negative, appeared to readily explai