Molecular biology of parathyroid hormone.

Abstract

The entire biosynthetic pathway of PTH has been elucidated from the determination of the chromosomal location to the eventual secretion of the hormone from the cell. The human gene is present on the short arm of chromosome 11, and restriction site polymorphisms near the gene have been detected. The PTH genes and cDNAs have been isolated and characterized in the bovine, human, and rat species. The gene contains two introns, which are in the same position in each species, and dissect the gene into 3 exons that code, respectively, for the 5' untranslated region, the signal peptide, and PTH plus the 3' untranslated region. The mRNAs are about twice as long as necessary to code for preProPTH and contain a 7-methylquanosine cap at the 5' terminus and polyadenylic acid at the 3' terminus. The 5' termini of the bovine and human mRNAs are heterogeneous at the 5' terminus, the basis of which is two TATA sequences in the 5' flanking regions of the gene. In contrast, the rat gene contains a single TATA sequence and the mRNA has a single 5' terminus. The initial translational product of the mRNA is preProPTH, and the pre-peptide of 25 amino acids is equivalent to signal peptides of other secreted and membrane proteins. The genes of the three species are very homologous in the region that codes for preProPTH. Substantial homology is also retained in the gene flanking regions, introns, and mRNA untranslated regions. Silent sites are also conserved more than would be expected, particularly between the human and bovine sequences. The bovine and human sequences are more closely related than the rat is to either the human or bovine. These studies of the basic molecular biology of PTH will provide the framework for future analysis of significant biological and medical questions. In vitro mutagenesis techniques should soon provide information about the elements of the gene involved in regulating transcription and about functional elements of the signal peptide. Eventually, signals involved in directing the ProPTH molecule to secretory granules as well as the biologically active regions of PTH, itself, will be examined by these methods. The molecular biological studies, combined with the development of dispersed cell cultures, provide the opportunity to study the effects of chronic changes in calcium on gene transcription and mRNA metabolism. The restriction site polymorphisms associated with the human PTH gene will allow a search for correlations between PTH gene structure and parathyroid disease.(ABSTRACT TRUNCATED AT 400 WORDS)