Human development is the summation of individual biochemical processes, each genetically programed to function in a systematic way, leading to the final expression and localization of an enzyme or protein. The development and localization of an enzyme require several genes which function as processing, temporal, architectural, targeting and receptor genes acting on a structural gene product. Inherited lysosomal enzyme disorders associated with abnormal development provided excellent models for studying the different numbers and types of genes required for the development of an enzyme. This study is designed to dissect, identify and characterize several new genes necessary for the final realization of a lysosomal enzyme. To accomplish this, 2 sets of lysosomal enzyme disorders will be studied: the mucolipidoses and the arylsulfatase A deficiency disorders. Each involve several affected gene all of which are required for the development of a lysosomal enzyme. The mucolipidoses (ML) consist of MLII and MLIII characterized by the golgi GlcNAc-P- transferase (GNPT) deficiency affecting the biosynthesis and localization of lysosomal enzymes. We have identified at least 3 genes that are required. The arylsulfatase-A deficiency disorders consist of metachromatic leukodystrophy, the multiple sulfatase deficiency disorder, the pseudo deficiency disorder, and the activator deficient disorder. Arylsulfatase-A is also deficient in the mucolipidoses. Our evidence suggests at least 10 genes involved in the final expression of arylsulfatase-A (ARSA). Therefore, this study has the potential of dissecting and identifying at least 10 new genes involved in the processing, targeting and development of lysosomal enzymes, in general, and ARSA, in particular. Somatic cell studies will genetically dissect and identify the genes. Genetic, biochemical, immunological, and molecular studies are proposed to characterize the genes and enzymes. Large families have been identified for mucolipidosis gene linkage studies. Our evidence indicates several types of genes, including structural, processing, targeting, temporal and receptor. Cloned genes will be used to characterize GNPT organization, disease- associated mutants, and gene expression. All markers developed will be available for genetic counseling, population screening, gene mapping, and diagnosis. These studies will describe involved in the expression, processing, and targeting of lysosomal enzymes, which will contribute basic information for human development and genetics and the biosynthesis of the lysosome.
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