COMPARISON OF THE FUNCTIONAL-PROPERTIES OF 3 DIFFERENT TRUNCATED THYROID-HORMONE RECEPTORS IDENTIFIED IN SUBJECTS WITH RESISTANCE TO THYROID-HORMONE

The tau4 domain in the extreme carboxyl (C) terminal region of thyroid hormone receptor (TR) is important to transactivation. We identified three truncated TR beta 1s with 11 (F451X), 13 (E449X) and 16 (C446X) amino acid deletions within this domain in subjects with resistance to thyroid hormone (RTH). F451X and C446X were found in a 6-year-old Jap anese girl and a 31-year-old American male, respectively, who had both severe mental retardation. E449X was identified in a 16-year-old Japa nese boy with no remarkable clinical symptoms except for goiter. Trans ient expression study revealed that all three mutants had negligible T 3 binding and transcriptional activities. Each mutant TR beta 1 exhibi ted not only very strong dominant negative activity against wild TR be ta 1, but also marked silencing activity. Interestingly, the dominant negative activity and silencing activity were significantly stronger i n F451X than in E449X and C446X (P < 0.05). Gel-shift experiments reve aled no apparent differences in homodimer formations of wild-type or m utant TR beta 1 proteins and in heterodimer formations with retinoid X receptor (RXR). These observations indicate that the tau4 domain affe cts diverse TR functions, and that the region between 11 and 13 C-term inal amino acids influences ligand-independent TR functions, including dominant negative and silencing activities. The central nervous syste m involvement is not necessarily determined by the dominant negative p otency of the mutant TR beta 1 and other environmental or genetic fact ors may influence the RTH manifestations. (C) 1998 Elsevier Science Ir eland Ltd. All rights reserved.