A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2

Abstract

The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA, differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM_199334 | p.(E173G), NP_955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor.

What is the Role of Thyroid Hormone Receptor Alpha 2 (TRα2) in Human Physiology?

“…In contrast to all other studies, we recently reported a THRA mutation that resulted in a gain-of-function in both isoforms 23 . A mutated glutamate-to-glycine residue in the first helix of the LBD had a promoting effect on T3-inducible TRα1 activity but also resulted in a gain-of-antagonistic effect for TRα2.…”

“…Recently, we described a novel heterozygous point mutation that enhances the function of both TRα isoforms, TRα1 and TRα2 leading to increased T3-activation of TRα1 and increased antagonism of TRα2 [23]. This novel mechanism in RTH due to THRA mutations brings the TRα2 splice variant into focus and raises further interest in its physiological function.…”

TRα2—An Untuned Second Fiddle or Fine-Tuning Thyroid Hormone Action?

“…Moreover, the C-terminal domain of α2 was demonstrated to be sufficient for the inhibition of transactivation mediated by the estrogen receptor without requiring the N-terminal DBD [58], but it does not inhibit the binding of TRα1 to TREs [59]. Additionally, a recent study revealed a mutation in a patient, affecting both TRα1 and TRα2 [76]. This point mutation is located outside the DBD and enhances the DNE of TRα2, suggesting enhanced cofactor binding rather than affecting DNA binding [76].…”

Thyroid Homeostasis: An Intricate Network of Production, Transport, Metabolism and Receptors Interaction

“…Most of these are located in the ligand binding domain of the carboxyl terminal portion of THRA1, causing a receptor loss of function, i.e., inability to bind the active form of TH, triiodothyronine (T3). Paisdzior et al [ 2 ] described a new variant of THRA located between the DNA and the ligand binding domain, thus affecting both THRA1 and THRA2. Interestingly, patients carrying this variant experience symptoms of hypo- and hyper-thyroidism.…”