title: Periodically hyperthyroid phenotype in thyroid hormone resistance is associated with mutation D322N in the thyroid hormone receptor beta gene: transcriptional properties of the mutant and the role of retinoid X receptor.
abstract: We report a point mutation in the ligand-binding domain of the TR beta 1 gene in an affected patient and his daughter. The phenotype was borderline hyperthyroid with periodic aggravation of symptoms. In the cognate variant TR beta (TR beta-CN) amino acid codon 322 was exchanged from aspartic acid to asparagine. TR beta-CN revealed strongly decreased T3-binding activity. At low T3 levels TR beta-CN transactivated a palindromic thyroid hormone response element (TRE-PAL) only to a limited extend, whereas full activity was retained at a high T3 concentration. At low T3 levels, TR beta-CN exerted a dominant negative effect on wild-type TR beta, whereas this effect was diminished in the presence of high T3 concentrations. TR beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T3, whereas addition of 9cis-retinoic acid (9c-RA) resulted in the transactivation of TRE-PAL through RXR beta independently of the presence of TR beta-CN. In conclusion, the time dependent variable THR phenotype of patient CN might be influenced by the differential expression of RXRs and the T3 and 9c-RA hormonal status.
authors.affiliation: Abteilung Innere Medizin I, Medizinische Klinik und Poliklinik Universität Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Behr
authors.forename: U
authors.initials: U
authors.lastname: Loos
mesh_terms: D000328:Adult; D002675:Child, Preschool; D003062:Codon; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics*; D008297:Male; D010641:Phenotype; D017354:Point Mutation; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D047488:Retinoid X Receptors; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D003062:Codon; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014284:Triiodothyronine