Human development is the summation of many individual biochemical processes, each genetically programed to function systematically, leading to the final expression of an enzyme or protein. Certain inherited lysosomal enzyme disorders associated with abnormal development provide excellent models for studying the genetic control of human enzyme expression and cellular localization. The molecular genetics of two groups of unique lysosomal enzyme disorders will be studied. They are the mucolipidoses and the arylsulfatase-A deficiency disorders. Genetic variants indicate that multiple genes with structural, processing, and other functions are altered for both groups. The mucolipidoses consist of mucolipidosis II and III characterized by a G1cNAc-P transferase deficiency that affects the biosynthesis and localization of many lysosomal enzymes. We have identified at least 3 genes that are involved in G1cNAc-P transferase expression. 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. Evidence suggests perhaps 4 genes involved in the expression of arylsulfatase-A. Somatic cell genetic studies will identify the genes involved in the mucolipidoses and the arylsulfatase-A deficiency disorders. Biochemical, immunological, and molecular studies will characterize each gene. Evidence indicates several types of genes, including structural and processing genes. G1cNAc-P transferase and arylsulfatase-A will be purified and antibodies made. G1cNAc-P transferase and arylsulfatase-A structural genes will be cloned using different alternatives. The cloned probes will be used to determine gene organization; the disease-associated lesions; and gene expression in structural and non-structural gene variants. The biochemical, immunological, and molecular markers, including DNA polymorphisms, produced will be available for genetic counseling, population screening, gene mapping, and diagnosis. These studies will describe genes involved in the expression of lysosomal enzymes, which will contribute basic information for human development and genetics.
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