The exon/intron organization and the structure of the 5' flanking region of the human thyrotropin receptor gene (hTSH-R) were determined. The hTSH-R gene spans more than 60 kb and is split into ten exons. The extracellular domain is encoded by the first nine exons and part of the last exon, whereas the transmembrane and intracellular domains are encoded in totality by the last exon. The leucine-rich repeats of the extracellular domain are encoded as monomers or multimers by separate exons. The TSH receptor gene seems to have arisen by insertion of a DNA sequence encoding repeated leucine-rich elements between the regions encoding the extracellular and the transmembrane domains of a proto-receptor gene ressembling the intronless beta adrenergic receptor genes. Primer extension and S1 mapping experiments identified three transcription start sites. In the hTSH-R gene, the main site was located 157 bp upstream from the start of translation. The promoter region is very GC-rich and contains multiple SP1, ETF and AP2 binding site consensus sequences.