The Human Thyrotropin β-Subunit Gene Differs in 5′ Structure from Murine TSH-β Genes

The gene encoding the β-subunit of human thyrotropin (hTSH-β) was isolated, and its nucleotide sequence was determined. The gene is 4.3 kb in length, consists of three exons and two introns, and is present as a single copy as determined by Southern blot analysis of total genomic DNA. The protein coding portion of the gene, which includes exons 2 and 3, was isolated from a human genomic phage library, while exon 1, which encodes only 5′ untranslated mRNA sequence, was isolated from a plasmid library of size-selected genomic DNA fragments. Here we describe the isolation of the 5′ untranslated exon of the hTSH-β subunit and 5′-flanking region. The structure of the hTSH-β gene is very similar to the previously characterized TSH-β genes from mouse and rat. The genes from all three species have two distinct promoter regions, but while both promoters are utilized by the murine TSH-β genes, the human TSH-β gene apparently utilizes only the proximal promoter for transcription initiation. A striking difference in hTSH-β gene structure compared to the murine genes is that exon 1 of the human gene is 36 nucleotides. An analysis of the mouse, rat, and human exon 1 and 5′-flanking region shows a high percentage of sequence homology, with the exception of a 9-nucleotide insertion 13 bases 3′ from the proximal TATA box found in the human gene but not found in the other two species. We propose that this insertion results in the additional length of human exon 1 compared to the mouse and rat genes. By isolating the promoter region of the hTSH-β gene, we can begin to identify specific sequences involved in the regulation of hTSH gene expression.