Heritable Disorders of Connective Tissue

Abstract

The Marfan syndrome, Ehlers—Danlos syndrome, and osteogenesis imperfecta are systemic genetic disorders of connective tissue. The wide variability of expression has led to the delineation of distinct phenotypic types within each of the three disorders. The Mendelian nature of all three disorders was established earlier this century, and their molecular basis and pathogenesis have been studied extensively during the past 20 yr. Mutations in genes encoding structural molecules present in the extracellular matrix of the connective tissue and their modifying enzymes have been identified. In the Marfan syndrome, mutations have been found in the FBN 1 gene encoding a large glycoprotein, fibrillin-1. In osteogenesis imperfecta, mutations have been found in the COL1A1 and COL1A2 genes encoding the two constituent protein chains of collagen type I. A variety of mutations in the genes encoding collagen type I, collagen type III, collagen type V, and certain collagen-modifying enzymes have been causally linked to the different types of the Ehlers—Danlos syndrome. Despite the dizzying variety of genes and mutations described, at least one common mechanism underlies the pathogenesis of each disorder. The abnormal protein chain appears to exert a dominant negative effect that impairs the structure and function of the collagen fibers or the elastin-associated microfibrils.