A mutant thyroid hormone receptor beta 1 identified in a patient with resistance to thyroid hormone inhibits the activities of not only the wild-type TRs, but also other nuclear receptors.
Although mutations of human thyroid hormone receptor beta (hTR beta) have been associated with resistance to thyroid hormone (RTH), the molecular basis by which the mutant TRs cause the various clinical symptoms is unknown. We show here that a mutant TR beta [corrected] identified in a patient with RTH inhibited the transcriptional activities of, not only the wild-type TR beta, but also other nuclear receptors including retinoid X receptor alpha (RXR alpha), vitamin D3 receptor (VDR) and retinoic acid receptor (RAR alpha). We provide evidence that these inhibitions by the mutant TR beta [corrected] occur by different mechanisms. Namely, the mutant TR beta interferes with VDR and RAR alpha by competition for binding to the corresponding response elements, but the pathway through RXR alpha is mainly inhibited by squelching of RXR alpha in solution. These findings suggest that in patients with RTH, not only the T3 responsive genes but also other responsive genes are inhibited by the mutant TRs, which might explain the variety of clinical symptoms in RTH.
Miyoshi
Y
Y
Department of Medicine and Clinical Science, Kyoto University School of Medicine, Japan. ymiyoshi@mail.med.upenn.edu
Nakao
K
K
D002648:Child; D002762:Cholecalciferol / Q000037:antagonists & inhibitors / Q000235:genetics; D004351:Drug Resistance; D005260:Female; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D047488:Retinoid X Receptors; D017384:Sequence Deletion; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D014158:Transcription, Genetic
D009687:Nuclear Proteins; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002762:Cholecalciferol