PATHOLOGY OF INBORN SKELETAL DISEASES

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Underlying structural defects of collagen are being sought in human connective tissues diseases. Of particular interest are those inborn disorders that affect the musculoskeleton, the more common ones being the Ehlers-Danlos syndromes, osteogenesis imperfecta, and Marfan's syndrome. A rich source of such rare tissues is available to us here and through collaborative contacts. Our primary approach is direct analysis of tissue matrix collagens by biochemical techniques. A portion of effort is spent screening promising new cases, but the main effort is devoted to follow-up studies in depth on identified collagen mutants. Though collagen disorders are the prime target, signs of proteoglycan defects would be pursued. A major goal is to gain unique insights on the relationship between structure and function of collagen, as well as helping detect, treat and prevent these skeletal disorders. Collagen cross-linking receives keen attention since cross-linking defects are common to many of the known diseases of the collagen molecule, and seems a good index of structural integrity. Techniques include slabgel electrophoresis and reverse phase HPLC chromatography of collagen polypeptides and derived fragments, and electronmicroscopy of collagen fibrils and cells in affected tissues. Where appropriate skin fibroblasts will be grown to characterize procollagen products. Appropriate tissue specimens will be frozen for future DNA and RNA analyses by collaborators should defects be indicated at the protein level. Specific cases for follow-up identified in the last two years by tissue screening include: 1) a new case of EDS VII in which a short deletion spanning the Alpha2(I)-chain amino-telopeptide domain is indicated; 2) a new case of EDS VI with no hydroxylysine in skin and lysyl pyridinoline replacing hydroxylysyl pyridinoline cross-links in cartilage; 3) two lethal newborn cases of spondylepiphyseal dysplasia in which a structural mutation of Alpha1(II) is present; 4) achondrogenesis type II (Langer-Saldino) that totally lacks type II collagen in cartilage; and 5) bone from several cases of osteogenesis imperfecta. In addition we will screen for cross-linking abnormalities in aortic collagen of Marfan's patients. Inborn disorders that impair the structure and development of the skeleton account for a significant fraction of the 12 million Americans who have birth defects. Collagen abnormalities will account for a significant number of these.