We propose a program of research directed toward an understanding of the means by which abnormalities of certain regions of the human genome cause mental retardation and developmental defects. The emphasis will be on the human chromosomes X, 15 and 17, and in addition those most commonly involved in chromosomal aneuploidy. The research planned utilizes a wide range of techniques including fluorescent in-situ hybridization (FISH), molecular cloning and sequencing, cytogenetics, somatic cell genetics, pedigree analysis and protein biochemistry, and fluorescence activated chromosome/cell sorting. These state of the art techniques will be used to dissect chromosomal regions in order to isolate and/or further characterize genes and their encoded protein products which are altered by mutation to yield the following genetic diseases: abnormal cognitive development in duchenne dystrophy, Prader Willi syndrome, and Retinitis Pigmentosa. Toward abnormal cognitive development in duchenne dystrophy, dystrophin will be localized in the brain and those proteins with which it interacts isolated. the function within normal brain may reveal insights into normal CNS development in regard to cognitive function. Equally important will be the gene/s in proximal 15q which are required to be paternally inherited germinally, without which contribution there is abnormal development resulting in Prader-Willi syndrome. In addition, we propose to identify and characterize those X-linked genes involved in Retinitis Pigmentosa. A new project is proposed which will have more direct clinical applications. The new project aims at improving the current methods for prenatal diagnosis. A novel means to detect chromosomal aneuploidy in fetal cells detected in maternal circulation will be enhanced, with the anticipation that such technology can be transferred to other diseases. Overall, we propose a coordinated effort of studying human genetic disease, and how it impacts on normal development and health.
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