Identification of a novel human thyroid hormone receptor β isoform as a transcriptional modulator

Thyroid hormone exerts a pleiotropic effect on development and homeostasis. A novel thyroid hormone receptor β isoform (hereafter referred to as TRβ4) 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 TRβ. The corresponding sequence of this insertion exists within the 5th intron of the human TRβ gene and consensus splice sequences were found at the junction sites. RACE analysis revealed that TRβ4 is a carboxyl-terminal splicing variant of TRβ1. RT-PCR and Northern blot analyses indicate that TR β4 mRNA is expressed in various human tissues, and especially abundant in testis and skeletal muscle. The TRβ4 protein was unable to bind thyroid hormone (T3) and transient transfection assays demonstrate that TRβ4 construct does not mediate T3-dependent gene regulation. TRβ4 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.