The principal objectives of the proposed work are to use linkage studies, in silico gene identification, cartilage gene expression and mutation analysis of functional and positional candidates to identify the disease genes in osteochondrodysplasias of unknown etiology. The linkage studies will use families collected by outreach efforts and referral to the International Skeletal Dysplasia Registry (Core A). The disorders to be studied have been selected based on criteria that include their frequency, the likelihood that identification of the disease gene will reveal an essential component of an important biological pathway, the ability to use the molecular information to improve definition of the diagnostic features and inheritance pattern(s) within a phenotypic group and the relevance to studies under the other components of the Program Project. Through these studies, we will define new molecular mechanisms for the skeletal dysplasias and understand the normal functions of skeletal dysplasia disease genes.
The Specific Aims are to identify the loci and disease genes in three phenotypic groups: 1. Short rib polydactyly and asphxiatinq thoracic dysplasia. These two perinatal lethal disorders are among the most frequent lethal skeletal dysplasias. They have been grouped together in the classification of skeletal dysplasias based on shared phenotypic features and have been hypothesized to be part of a spectrum of disease that includes chondroectodermal dysplasia. We will test the hypothesis that they are either allelic or that the disease genes are components of a pathway. 2. Recessive osteogenesis imperfecta (Ol). Knockout mice with deficiency of Crtap have a defect in prolyl hydroxylation that leads to an undermineralized skeleton resembling osteogenesis imperfecta. The goal of this aim is to work in collaboration with the other Projects and Cores to identify human recessive Ol phenotypes with mutations in CRTAP. In cases where CRTAP is excluded, additional candidate loci will be considered, including a newly identified locus on chromosome 17q21-22. These interactive studies will facilitate the definition of both the molecular basis and the clinical and histological features that characterize novel mechanismsfor recessively inherited osteogenesis imperfecta. 3. Brachyolmia. Brachyolmia is a form of short trunk short stature with a characteristic platyspondyly and irregular margins of the vertebral bodies. The phenotype is clinically and genetically heterogeneous with dominant and recessive forms described. The goal of this aim is to use linkage studies to define the first brachyolmia locus and to determine the diagnostic features and natural history of the entity. Identification of a disease gene for dominant brachyolmia will promote clarification of the diagnostic features of each form and will help define the biological basis of the phenotype
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