The Skeletal Dysplasias

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DESCRIPTION (provided by applicant): The skeletal dysplasias are a group of more than 370 disorders that result in disproportionate short stature and/or skeletal deformities. Although they have long been considered to be generalized disorders of endochondral and/or membranous ossification, the extent of their heterogeneity and genetic basis is still being elucidated and their pathogenesis can now be investigated. This program project is directed toward a multidisciplinary investigation of the clinical, genetic, morphologic, biochemical, and molecular characteristics of the skeletal dysplasias. Specific aims include: 1. Expansion of the materials for study in the International Skeletal Dysplasia Registry. 2. Definition of the clinical and radiographic features and genetic heterogeneity of the skeletal dysplasias and elucidation of the natural history, growth characteristics, and complications of each of these disorders. 3. Improvement of methods for the antenatal diagnosis of prenatal-onset skeletal dysplasias. 4. Elucidation of the histological, histochemical, immunohistological, and ultrastructural characteristics of chondroosseous tissue in each of the skeletal dysplasias. 5. Identification of the disease genes in osteochondrodysplasias of unknown etiology, using linkage, positional cloning, and candidate gene approaches. 6. Correlation of the clinical, radiographic, and morphologic features of each skeletal dysplasia with their specific biochemical and molecular defects. 7. Development of a new Protein Biochemistry Core to provide specialized analytical methods, including protein mass spectrometry, to characterize the protein defects in human and mouse skeletal dysplasias. 8. Evaluation of the effects of post-translational modification of proteins on chondroosseous development. The program project is consisted of two core facilities, the International Skeletal Dysplasia Registry and the Protein Biochemistry Core, plus three integrated projects; (1) Clinical, pathophysiological and therapeutic studies; (2) Molecular studies in the skeletal dysplasias; and (3) Developmental studies in the skeletal dysplasias. The International Skeletal Dysplasia Registry, the largest such registry/database in the world, serves as an international resource for studying the skeletal dysplasias. A worldwide group of referring health professionals provide materials from clinically documented cases for these research projects are integrated to define a comprehensive understanding of the biological basis of these conditions.