Novel Mutation (T273R) in Thyroid Hormone Receptor β Gene Provides Further Insight into Cryptic Negative Regulation by Thyroid Hormone

Kaššák, Filip; Hána, V.; Saudek, V.; Kostrouchová, M.

doi:10.14712/fb2017063020060

Folia Biologica > Archive > 2017, Vol. 63 > Issue 2 > Novel Mutation (T273R) in Thyroid…

Fol. Biol. 2017, 63, 60-66

https://doi.org/10.14712/fb2017063020060

Novel Mutation (T273R) in Thyroid Hormone Receptor β Gene Provides Further Insight into Cryptic Negative Regulation by Thyroid Hormone

Filip Kaššák¹, V. Hána², V. Saudek³, M. Kostrouchová¹

¹Biocev, First Faculty of Medicine, Charles University, Vestec, Czech Republic
²3rd Medical Department, Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University, Prague, Czech Republic
³University of Cambridge Metabolic Research Laboratories, Wellcome Trust–Medical Research Council, Institute of Metabolic Science, Cambridge, United Kingdom

Received November 2016
Accepted February 2017

Production of thyroid hormone is precisely regulated in a negative feed-back mechanism that depends critically on thyroid hormone receptor β (TRβ). This mechanism decreases production of thyrotropin- releasing hormone (TRH) and thyrotropin (TSH) in the hypothalamus and pituitary gland in response to high levels of circulating thyroid hormones (TH). Despite the wealth of accumulated knowledge, it is still not clear how exactly this negative regulation is executed. The syndrome of resistance to thyroid hormone (RTH), in which the levels of TH are not properly sensed, represents naturally occurring situations in which molecular components of this regulation are displayed and may be uncovered. TRβ, which is central to this regulation, is in the majority of RTH cases mutated in a way that preserves some functions of the receptor. Approximately 150 different mutations in TRβ have been identified to date. Here, we hypothesized that additional pathogenic mutations in TRβ are likely to exist in human population and analysed clinical cases with suspected RTH. In keeping with our prediction, analysis of 17 patients from nine families led to identification of four presumed pathogenic mutations of TRβ, including a previously unknown mutation, T273R. This suggests that threonine 273 is likely to be critical for the normal function of TRβ, possibly due to its role in helix 12 mobility and interaction with coactivators, and thus supports the concept that TRβ-dependent trans-activating function is necessary for the inhibition of TRH and TSH expression in response to elevated levels of TH.

Keywords

thyroid hormone receptor β, negative regulation, negative feedback regulation, syndrome of resistance to thyroid hormone, RTH, T273R.

Funding

This work was supported by the European Regional Development Fund “BIOCEV – Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University in Vestec” (CZ.1.05/ 1.1.00/02.0109) (Start-Up Grant to the group Structure and Function of Cells in Their Normal State and in Pathology – Integrative Biology and Pathology (5.1.10)) and the LQ1604 National Sustainability Programme II (Project BIOCEV-FAR) from the Ministry of Education, Youth and Sports of Czech Republic; grant PRVOUK-P27/LF1/1 from Charles University, grants SVV 260023/2014, SVV 260149/2015, SVV 260257/2016 and SVV 260377/2017 from Charles University.