DEOXYRIBONUCLEIC-ACID BINDING AND TRANSCRIPTIONAL SILENCING BY A TRUNCATED C-ERBA-BETA-1 THYROID-HORMONE RECEPTOR IDENTIFIED IN A SEVERELY RETARDED PATIENT WITH RESISTANCE TO THYROID-HORMONE

We describe the analysis of a thyroid hormone receptor (TR) beta causi ng resistance to thyroid hormone, the patient exhibiting hypothyroid s ymptoms (severe mental retardation, hypoactivity, obesity) and hyperth yroid symptoms (tachycardia, low serum cholesterol) and, additionally, relative early puberty, advanced bone age, and short stature. The pat ient was heterozygous, with a point mutation producing a premature sto p-codon in TR beta-gene exon 10, resulting in a 28-amino acid carboxy- terminal deletion in the cognate TR beta (TR beta-EZ). T-3 binding was abolished. Homodimer binding of TR beta-EZ to DR4- and F2-T-3 respons e elements (TREs) was weaker, and to a palindromic TRE (PAL) was stron ger than that of wild-type TR beta (TR beta-WT) in the absence of T-3. T-3 dissociated TR beta-WT, but not TR beta-EZ homodimer, from DR4, F 2, and Pal. Heterodimerization of TR beta-EZ with retinoid x receptor beta was seen. TR beta-EZ repressed basal thymidine kinase-promotor ac tivity, coupled to DR4, F2, or PAL. Silencing of basal gene transcript ion via PAL was weaker, and via DR4 and F2 was more pronounced, compar ed with TR beta-WT. TR beta-EZ had a strong dominant negative effect o n TR beta-WT, attenuated in a TRE- and cell-specific manner by high T- 3 concentrations. Finally, the degree of TR beta-EZ homodimer-binding affinity to DNA did not correlate with the degree of transcriptional d ominant negative activity.