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The TRH receptor gene is a single copy gene containing three exons and two introns and was assigned to the chromosome 8q23. A patient with congenital central hypothyroidism due to the mutations of the thyrotropin-releasing hormone receptor gene has been reported by Collu, et al: in 1997. His sole manifestation was short stature, and his plasma TSH and prolactin levels did not increase in TRH test. He was found to be a compound heterozygote of the mutations of the TRH receptor gene. Expression study using COS1 cells and HEK293 cells revealed that both mutations reduced or abolished the receptor activity.

We measured amounts of thyrotropin-releasing hormone receptor (TRHR) mRNA in human pituitary tumors, and found a novel transcript of the TRHR gene. Competitive PCR revealed expression of the TRHR mRNA in all pituitary adenomas examined, and its level was variable and similar to that in the normal pituitary. When the C-terminal region was amplified by PCR, an additional short product was observed. Cloning and sequence analysis of this short fragment revealed that the deleted sequence corresponded exactly to the 5' sequence of exon 3, indicating alternative splicing of the TRHR mRNA. This alternative splicing resulted in a frame shift yielding a C-terminal truncated protein (HTRHR2) on translation. The mRNA ratio of the HTRHR2 versus the wild-type was significantly different among pituitary tumors.

Thyrotropin-releasing hormone (TRH) receptor (TRHR) cDNAs have been cloned from several species since 1990. Sequence analysis of these cDNAs showed that TRHR belongs to the family of G-protein coupled receptors containing seven transmembrane domains. The human gene spans more than 30 kb and contains three exons and two introns, which located on chromosome 8q23. Several new evidences have been reported including primary structure of TRHRs, distribution of TRHR mRNA, three dimensional structure of the TRH binding pocket, structure of the TRHR gene promoter, G-proteins and TRHR etc. Furthermore, a patient with central hypothyroidism caused by compound mutations of the TRHR gene and a novel transcript of TRHR gene in the pituitary have been recently reported.

1) We successfully cloned a human thyrotropin-releasing hormone receptor (TRH-R) gene. The human TRH-R consists of 398 amino acids and is a member of the G protein-coupled receptor family. The gene has a single intron in the coding sequence. Although highly homologous to the rat and mouse TRH-Rs, the human TRH-R has several differences in the carboxyl-terminal structure. 2) We next studied the effect of thyroid status on TRH-R mRNA levels both in vivo and in vitro. TRH-R mRNA levels in hypothyroid rats were increased significantly, while no significant changes were observed in vitro. The data indicate that thyroid hormone may regulate TRH-R mRNA levels in different manners in vitro and in vivo.