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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



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



Experimental and Clinical Endocrinology & Diabetes 104 Suppl 4: 111-116



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 T-3-binding activity. At low T-3 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 T-3 concentration. At low T-3 levels, TR-beta-CN exerted a dominant negative effect on wild-type TR-beta, whereas this effect was diminished in the presence of high T-3 concentrations. TR-beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T-3, 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 T-3 and 9c-RA hormonal status.

Accession: 009172973

Download citation: RISBibTeXText

PMID: 8981016

DOI: 10.1055/s-0029-1211716


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