Thyroid hormone exerts a pleiotropic effect on development and homeostasis. A novel thyroid hormone receptor beta isoform (hereafter referred to as TR beta 4) was cloned using PCR from a human pituitary cDNA library as a template. Analysis of the PCR products revealed a 137-bp insertion, which contains a stop codon in the middle, between the 5th and 6th exons that encode the ligand-binding domain of TR beta. The corresponding sequence of this insertion exists within the 5th intron of the human TR beta gene and consensus splice sequences were found at the junction sites. RACE analysis revealed that TR beta 4 is a carboxyl-terminal splicing variant of TR beta 1. RT-PCR and Northern blot analyses indicate that TR beta 4 mRNA is expressed in various human tissues, and especially abundant in testis and skeletal muscle. The TR beta 4 protein was unable to bind thyroid hormone (T3) and transient transfection assays demonstrate that TR beta 4 construct does not mediate T3-dependent gene regulation. TR beta 4 weakly but significantly inhibited transcription mediated by functional TR. Thus, this novel isoform may modulate hormone action as an endogenous antagonist in the tissue or cellular context.
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