Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes
Introduction
Thyroid hormone (TH) is crucial for normal development and metabolism of virtually all tissues. Its important developmental role is best illustrated by the severe consequences of untreated congenital hypothyroidism which results in growth impairment and intellectual disability (Grüters and Krude, 2012). The thyroid gland mainly produces the inactive prohormone thyroxine (T4) and to a lesser extent the bioactive hormone 3,3′,5-triiodothyronine (T3). The main effects of TH are exerted through binding of T3 to its nuclear receptor (thyroid hormone receptor, TR), which functions as a ligand-dependent transcription factor. The main receptor isoforms are TRα1 and 2 and TRβ1 and 2, which differ in their tissue distribution (Cheng et al., 2010). TRα1 and TRβ1 and 2 are bona fide T3-interacting receptors. The amount of T3 available for receptor binding is importantly determined by the intracellular deiodinases (DIO1-3), which facilitate the activation of T4 to T3 (DIO1 and DIO2) and/or the inactivation of T4 to 3,3′,5’-triiodothyronine (rT3) and of T3 to 3,3’-diiodothyronine (3,3′-T2; DIO1 and DIO3). In addition, decarboxylation of the alanine side-chain, resulting in the formation of iodothyronamines, and subsequent oxidative deamination, resulting in the formation of iodothyroacetic acids, comprise another mechanism of iodothyronine metabolism (Wood et al., 2009, Hoefig et al., 2016). Importantly, some of these metabolic intermediates have been found to exert biological effects, of which the thyromimetic effects of 3,3′,5-triiodothyroacetic acid (Triac) have been most extensively studied (Groeneweg et al., 2017 submitted). The transport of TH across the plasma membrane by membrane transporter proteins is another crucial step that governs intracellular TH concentrations (Hennemann et al., 2001). Many transporters have been shown to facilitate TH transport, of which the monocarboxylate transporter (MCT)8 is the most specific TH transporter identified to date (reviewed in Visser, 2007; Bernal et al., 2015, Kinne et al., 2010). Thus, cellular TH action requires adequate function of (1) TH transporter proteins, (2) deiodinases and (3) nuclear receptors.
Defects in any of these processes give rise to distinct clinical syndromes, collectively called disorders of TH signaling or resistance to thyroid hormone (RTH) syndromes (Refetoff et al., 2014, Dumitrescu and Refetoff, 2013). So far, clinical phenotypes have been associated with mutations in TRβ (reviewed in Dumitrescu and Refetoff, 2013), TRα (Bochukova et al., 2012, Van Mullem et al., 2012) and MCT8 (Friesema et al., 2004, Dumitrescu et al., 2004). No mutations in deiodinases have been identified yet, although mutations in SECIS-binding protein 2 (SBP2) and selenocysteine transfer RNA, both required for the adequate production of deiodinases and other selenoproteins, have been reported (reviewed in Fu and Dumitrescu, 2014, Schoenmakers et al., 2016).
Compounds with thyromimetic potency but with different (bio)chemical properties compared to T3 may hold therapeutic potential in RTH syndromes by bypassing defective transporters or binding to mutant TRs. The application of bioactive TH metabolites or synthetic TH analogues has been studied in many different contexts (e.g. heart failure or primary hypothyroidism). This review will focus on the (putative) application of these compounds in the treatment of RTH syndromes.
Section snippets
Properties of TH analogues used in RTH syndromes
The TH analogues studied in the context of RTH syndromes (RTH-β and MCT8 deficiency) are 3,3′,5-triiodothyroacetic acid (Triac), 3,3′,5,5’-tetraiodothyroacetic acid (Tetrac),3,5-diiodothyropropionic acid (DITPA) and dextro(D)-T4 (choloxin). Tetrac and Triac are naturally occurring metabolites of TH in humans, although present at ∼50-fold lower concentrations than T4 and T3, respectively (Crossley and Ramsden, 1979, Gavin et al., 1980, Menegay et al., 1989). Their major serum binding protein is
Background and rationale of TH analogue therapy
Heterozygous mutations of TRβ are the common genetic cause of RTHβ (Weiss et al., 2016). So far, over 3000 cases have been identified and about 132 distinct pathogenic mutations have been identified in the TRβ gene (Weiss et al., 2016). These mutations generally cluster within three distinct hot spots (Fig. 1). Mutant receptors exhibit a diminished T3 binding affinity and/or impaired interaction with co-regulators involved in the mediation of T3 action and generally display a dominant negative
TH analogues and RTHα
Mutations in the TRα isoform have been recently identified (Bochukova et al., 2012, Van Mullem et al., 2012). The resulting phenotype has been coined RTHα, predominantly characterized by abnormal bone development, constipation, anemia and various degrees of neurocognitive impairments (Moran and Chatterjee, 2015). These clinical features are accompanied by subtle changes in thyroid parameters, including low-normal serum (F)T4 and high-normal serum (F)T3 concentrations in the context of normal
Background and rationale of TH analogue therapy
The only TH transporter that is currently linked to clinical disease is MCT8 (Friesema et al., 2004, Dumitrescu et al., 2004). Mutations in MCT8 result in AHDS, characterized by severe intellectual disability and abnormal serum thyroid function tests (TFTs), including elevated serum T3, reduced rT3 and low or low-normal (F)T4 levels in the presence of a normal to high-normal TSH. MCT8 has been found to be essential for TH transport across the blood-brain-barrier (BBB) and into neuronal cells (
TH analogues and defects of deiodination
Mutations in SBP2 and selenocysteine transfer RNA disturb deiodination of TH and several of its metabolites and produce a typical biochemical thyroid fingerprint (elevated serum T4 and rT3 and low to low-normal T3 levels in the presence of normal or slightly elevated TSH levels). However, it is unclear which features, if any, can be attributed to defective TH signaling. Several reports mention beneficial effects of L-T3 treatment on body height (Di Cosmo et al., 2009b, Azevedo et al., 2010,
Concluding remark
The thyromimetic action and hence applicability of TH analogues is importantly determined by their receptor isoform specificity, tissue availability and metabolic clearance. These analogue specific properties largely determine their applicability in the treatment of RTHβ syndromes. In humans, Triac has a role in the treatment of RTHβ, in particular for patients harboring mutations in clusters 1 or 2 of TRβ. Advancing insight into the protein structure of the TR isoforms and substrate-receptor
Conflict of interest
The authors declare that they have no conflicts of interest.
All authors have nothing to disclose.
Acknowledgments
This work was supported by a grant from the Netherlands Organisation for Health Research and Development (project number 113303005) (to WEV) and from the Sherman Foundation (to WEV).
References (112)
- et al.
Comparison of effectiveness of thyrotropin-suppressive doses of D- and L-thyroxine in treatment of hypercholesterolemia
Am. J. Med.
(1984) - et al.
Selective activation of thyroid Hormone signaling pathways by gc-1: a new approach to controlling Cholesterol and body weight
Trends Endocrinol. Metab.
(2004) - et al.
A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor
Chem. Biol.
(1998) - et al.
Serum tetraiodothyroacetate (T4A) levels in normal healthy euthyroid individuals determined by gas chromatography-mass fragmentography (GC-MF)
Clin. Chim. Acta
(1979) - et al.
A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene
Am. J. Hum. Genet.
(2004) - et al.
The syndromes of reduced sensitivity to thyroid hormone
Biochim. Biophys. Acta
(2013) - et al.
Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation
Lancet
(2004) - et al.
Inherited defects in thyroid hormone cell-membrane transport and metabolism
Best. Pract. Res. Clin. Endocrinol. Metab.
(2014) - et al.
Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRbeta(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone
Bioorg Med. Chem.
(2005) - et al.
Essential molecular determinants for thyroid hormone transport and first structural implications for monocarboxylate transporter 8
J. Biol. Chem.
(2010)