Endocrine Abstracts (2012) 28 OC1.4

The thyroid hormone receptor-coactivator interface mediates negative feedback regulation of the human pituitary-thyroid axis

Carla Moran1, Catherine Mitchell1, Maura Agostini1, Erik Schoenmakers1, John Gregory2, Mark Gurnell1 & Krishna Chatterjee1

1Institute of Metabolic Science, University of Cambridge, Cambridgeshire, United Kingdom; 2Department of Child Health, Wales School of Medicine, Cardiff, United Kingdom.

Corepressors and coactivators of thyroid hormone receptor-mediated function facilitate repression and transactivation of positively-regulated target genes respectively, but their role in negative regulation is not understood. A 13 yr old boy, born at 31 weeks gestation, was jittery at birth, with neonatal respiratory distress. Childhood features included poor weight gain, heat intolerance, tachycardia and hyperactivity. Ongoing problems are low frequency hearing loss, poor sight, impaired coordination and learning disability. His circulating free thyroid hormones are consistently elevated (FT4 47.1 pmol/L (RR 9.8–23.1), FT3 13.7 pmol/L (RR 3.5–6.5)) together with non-suppressed TSH (8.0 mU/L (RR 0.35–5.50)) levels; parental thyroid function is normal. The proband is heterozygous for a novel mutation (E457Q) in the TRβ gene, involving a highly conserved residue located in its carboxyterminal transactivation domain; the mutation occurs de novo, with wild type parental TRβ sequence, consistent with their normal thyroid function. Although the mutant receptor binds T3 normally (WT Ka = 1.29×1010 M−1; E457Q Ka = 1.26×1010 M−1) hormone-dependent negative regulation (TSHα promoter) by E457Q TRβ is markedly impaired; in addition, when coexpressed, E457Q TRβ is a strong dominant negative inhibitor of WT receptor function. In protein-protein interaction assays, E457Q TRβ binds and dissociates from corepressors (NCoR, SMRT) normally; however, the mutant receptor fails to recruit coactivators (TRAP 220, SRC-1, RIP140, LCoR). Crystallographic modelling indicates that substitution of glutamine for the negatively-charged glutamic acid at codon 457 abrogates electrostatic receptor-coactivator interactions. Elevated thyroid hormones with non-suppressed TSH in the proband indicate impaired negative feedback in the pituitary-thyroid axis in vivo, consistent with impaired negative regulation of the TSHβ promoter by E457Q TRβ seen in vitro. Together these observations suggest that proteins recruited to the thyroid receptor-coactivator interface mediate negative transcriptional regulation of target genes in the human pituitary-thyroid axis.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: NIHR, Biomedical Research Centre.

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