COLLAGEN BIOSYNTHESIS IN CONNECTIVE TISSUE DISEASE

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Collagen is a major structural protein in the body, providing the framework for tissues such as skin, bone, tendon, cartilage, lung, cornea, and heart valve. Normal collagen biosynthesis requires a stringent regulation of a number of transcriptional, translational, and post-translational events including type-specific synthesis, hydroxylation of prolyl and Iysyl residues, glycosylation of hydroxylysyl residues, disulfide bond formation, secretion, cleavage of extension peptides, fibril formation, and cross-linking. Perturbation in any one step in this sequential process might be expected to result in structurally altered collagen, hence the disease associated with it. Abnormalities in collagen structure or biosynthesis are known to occur in a number of connective tissue diseases such as the Ehlers-Danlos syndrome, osteogenesis imperfecta, the Marfan syndrome, and cutis laxa. We propose to isolate a cDNA for lysyl hydroxylase in order to elucidate the molecular mechanism(s) of the enzyme defect in Type VI Ehlers- Danlos syndrome. We also propose to characterize the mutation causing the synthesis of an abnormal 2(I) collagen chain in a patient with the Marfan syndrome.