Difference in dominant negative activities between mutant thyroid hormone receptors α1 and β1 with an identical truncation in the extreme carboxyl-terminal tau4 domain

Although different expression patterns of thyroid hormone receptor (TR) α1 and β1 have been reported, no essential distinction has been established in their functions. Unlike the TRβ gene, a mutation in the TRα1 gene has never been found in patients with resistance to thyroid hormone (RTH). Previously we found a mutant TRβ with an 11-carboxyl (C)-terminal amino acid truncation (βF451X) in a girl with severe RTH. βF451X is a natural mutant with disruption of the transactivation domain, tau4, and it had very strong dominant negative activities. Based on the fact that the 46 amino acid sequence in the extreme C-terminal region is identical in TRα1 and TRβ, except for a C-terminal three amino acid extension of TRα1, we constructed a mutant TRα1 (αF397X) with the identical C-terminal truncation to βF451X, to study functional differences between TRα1 and β1. Both βF451X and αF397X had negligible T3 binding and transcriptional activities even with 1 μM T3. The dominant negative activities of the mutant TRs were remarkable and T3 response element (TRE)-dependent. Co-expression of βF451X decreased the CAT activity of either wild-type TRα1 or β1 at 100 nM T3 by ≈90% on the TRE-pal2 and 70% on DR4. αF397X inhibited the transcriptional activities of both wild-type TRα1 and β1 by ≈50% on TRE-pal2 and by 60% on DR4. The dominant negative potency of βF451X was significantly stronger than that of αF397X on the TRE-pal2, -DR4 and chicken lysozyme silencer F2, but similar on TRE-myosin heavy chain α and malic enzyme. No partiality for the TR subtypes was found in the dominant negative effects of βF451X and αF397X. Co-expression with RXR enhanced the dominant negative effects of αF397X, but not of βF451X. The results indicate that there are different dominant negative properties between αF397X and βF451X, which are TRE-dependent, despite their identical C-terminal truncation. Deletion in the tau4 domain might affect the receptor structures of TRα1 and β1 differently.