Catecholamine neurotransmitters have been implicated to have a role in the etiology of some diseases of the central nervous system, including dementia, Parkinson's disease, behavioral disorders. The activity of the catecholamine biosynthetic enzymes controls the level and availability of these important neurotransmitters. These enzymes, tyrosine hydroxylase, dopamine B-hydroxylase and phenylethanolamine N-methyltransferase, comprise a multigene family, sharing extensive homologies both in their protein structure and at the level of their genomic sequences. Elucidating the structural organization of the catecholamine enzyme genes is essential for understanding the regulation of these genes in the both normal and disease state. A major first step in this direction has involved the isolation of cDNAs encoding these enzymes. In the present studies, the structural organization of these genes will be investigated and ultimately related to the functional regulation of catecholamine biosynthetic pathway. The isolation and characterization of full-length cDNA clones is the next step toward this objective. The coding regions will be completely defined by the nucleotide sequence of the cDNAs for these enzymes. Using full length cDNA probes, the genomic sequences containing the catecholamines enzyme genes will be isolated. The size, distribution and structure of the intronic and exonic regions of the genomic DNA will be examined. Additionally, the regions flanking the catecholamine enzyme genes will be characterized, thereby providing an opportunity to identify regulatory regions in the primary genomic structures. A comparison of the non-coding regions will indicate whether sequence homologies for this multigene family extend beyond the regions coding for the enzyme proteins. Finally, the structural organization of the genes comprising this family will be investigated by studies on genomic DNA cloned into bacteriophage and cosmid vectors.
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