The genetic and cytogenetic basis of various diseases associated with mental retardation will be determined through an integrated application of such tools as tissue culture, hybrid cell techniques, enzymatic analyses, and cytogenetic studies. Emphasis will be placed upon developing an understanding of mammalian regulatory genes, assigning genes to specific chromosomes, methods of introducing exogenous DNA into cultured mammalian cells, isolation of intact lysosomes, preparation of purified lysosomal enzymes, development of new selective techniques for use with hybrid cells and studies of spindle microtubule protein. The results obtained will be used to elucidate the etiology and pathogenesis of various diseases associated with mental retardation and to develop new therapeutic approaches.