Collagen is the major structural protein of the body and as such provides the framework for all tissues including skin, bone, tendon, cartilage, lung, cornea, and heart valve. Proper collagen biosynthesis requires a precise orchestration of a number of transcriptional and post-translation steps including regulation of type-specific collagen biosynthesis, hydroxylation of proline and lysine, glycosylation of hydroxylysine, disulfide bond formation, transport to the extracellular space, enzymatic excision of extension peptides, fibril formation, and cross-linking. Perturbation in this sequential biosynthetic scheme might be expected to result in structurally altered connective tissue and disease. Individual abnormalities in collagen biosynthesis have been described in patients presenting clinically with Ehlers-Danlos syndrome, osteogenesis imperfecta, and cutis laxa. We propose to study collagen biosynthesis in skin fibroblasts obtained from patients with these study collagen biosynthesis in skin fibroblasts obtained from patients with these and other inherited disorders of connective tissue. The following parameters of collagen biosynthesis will be measured: (1) type-specific collagen synthesis, (2) synthesis of procollagen and processing of procollagen, (3) synthesis of glycosylated hybroxylysine, (4) synthesis of reducible cross-links, (5) levels of lysyl hydroxylase prolyl hydroxylase and lysyl, (6) levels of collagen specific mRNA, and (7) structure of collagen genes. It is hoped that these studies will allow us to better understand these diseases at a biochemical level. Such understanding is a prerequisite for rational prenatal diagnosis, genetic counseling, and therapeutic management.
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