Inborn molecular defects in collagen structure are being characterized in various skeletal diseases. The emphasis is on osteogenesis imperfecta, Ehlers Danlos syndrome and certain chondrodystrophies. Of particular interest are diseases that result in structural mutations of collagen expressed in the extracellular matrix and their effects or collagen polymerization and cross-linking. The application of micro- techniques in protein chemistry to tissue biopsies is the theme of the work. The goal with osteogenesis imperfecta is to understand better how a diversity of mutatiotis in type I collagen all result in brittle bone. By studying bone tissue (surgery and autopsy) from patients of known molecular defect, the degree to which mutations are expressed and persist extracellularly in cross-linked bone matrix will be examined. Is the disease principally one of collagen underproduction rather than the consequences of structurally inadequate collagen molecules forming the matrix? Likewise, the consequences of structural mutations and post-translational defects of collagen in Ehlers-Danlos syndromes VI ind VII will be defined in more detail. Efforts will be made to reveal inherited structural defects in cartilage-specific collagens (types II and IX) as the cause of curtain forms of chondrodystrophy, including the broadly-defined spondyloepiphyseal dysplasias and diastrophic dysplasias. The possibility that polymorphisms of the human type II collagen gene exist in the population, and perhaps account for observed natural variations in degree of cross-linking in human cartilage collagen, will be tested. Inherited mutations of type II collagen affecting cross-linking as a cause of familial osteoarthrosis will also be examined. The objective is to learn the importance of certain features of collagen structure, for example those that control cross-linking reactions, in determining function. Through an understanding of the effects of rare inborn mutations, so the normal properties of collagens and their variations can be better appreciated.
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