This Neurogenetics Center will use techniques in molecular genetics to increase our understanding of four inherited neurological diseases: neurofibromatosis (both central and peripheral forms), tuberous sclerosis, neuronal ceroid lipofuscinosis, and familial dysautonomia. Linkage analysis using DNA polymorphisms will be used to find marker sequences for defective genes in these diseases as a aid in genetic counseling and a first step in gene identification. Clinical, biochemical and neuroimaging studies will be undertaken to complement and extend genetic approaches. The intrinsic expression of defective genes for tuberous sclerosis and peripheral neurofibromatosis will be evaluated in cultured melanocytes from patients. Further, the clonal origin of these cells and regions of chromosomal homozygosity will be examined as an indication of whether somatic mutations underlie altered pigmentation in these diseases. Retrovirus-mediated gene transfer of nerve growth factor and the nerve growth factor receptor into fibroblasts will be used to study processing of these proteins in patients with familial dysautonomia. In addition, this gene transfer system will be used to deliver nerve growth factor to the rat central nervous system as a model for gene therapy and to study its actions there. High resolution magnetic resonance imaging will be used to provide new information in defining neuropathological changes in ceroid lipofuscinosis and lesions in unaffected carriers of the tuberous sclerosis gene. Dolichol metabolism will be studied in ceroid lipofuscinosis to aid in disease classification and to elucidate molecular etiology. This metabolism as well as altered lysosomal structure will also be analyzed in cultured fibroblasts under conditions of protease inhibition in an attempt to identify gene carriers. This research will employ genetics in concert with other disciplines in the neurosciences to improve our understanding of these diseases, and to provide new experimental approaches to the study of other inherited neurological diseases. Emphasis will be placed on the importance of disease classification, the need to detect unaffected gene carriers, the possibility of studying defective phenotypes in cultured cells and the potential effectiveness of gene transfer into the nervous system.
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