The glucuronidase gene complex (Gus) has been extensively studied previously. In addition to the structural gene, it contains regulatory loci determining the systemic rate of enzyme synthesis (Gus-u), the tissue specific developmental profile of enzyme synthesis (Gus-t), and the inducibility of glucuronidase in response to androgens (Gus-r). Mutants in these loci are maintained in congenic lines with a standard genetic background and will be used in conjunction with recently obtained cDNA clones. They will be compared to determine the DNA sequence organization of different (Gus) haplotypes, look for changes in chromatin structure that accompany regulation, and determine the levels of regulation by mRNA and transcription rate assays. Additional experiments will look for the gene product of the trans-acting (Gus-t) locus, continue work on the peptide structure of glucuronidase, and characterize new mutants that will aid in analysing this system as a general model of mammalian gene regulation. The significance of these experiments lies partly in the effort to understand the basic mechanisms of gene regulation in mammals and hence, by extension, in man and partly in the specific information we expect to develop that will be applicable to understanding lysosomal enzymes as a class. We know very little about mammalian regulatory genes beyond the fact that they some how control mRNA levels. We are ignorant of their detailed organization, structure and mechanisms of action; and we hope to provide relevant information on these questions. Lysosomal enzymes as a class are very important physiologically and have become paradigms of human genetic defects. None has been sequenced yet and, with the very recent exception of glucuronidase, none has been cloned. The studies of glucuronidase are likely to facilitate research on this group of proteins as a class.
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