Abstract
Thyroid hormone (TH) metabolism and action via binding to nuclear receptors are intracellular events that require the passage of TH across the plasma membrane. This process is mediated by specific TH transporters of which the monocarboxylate transporter 8 (Mct8) has received major attention. Mct8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain. In humans, inactivating mutations of the MCT8 gene (SLC16A2) are associated with severe forms of psychomotor retardation and abnormal TH serum levels (Allan-Herndon-Dudley syndrome). Surprisingly, Mct8 knockout (ko) mice do not exhibit overt neurological symptoms but fully replicate the unusual serum TH profile with highly increased serum T<sub>3</sub> in the presence of low serum T<sub>4</sub>. In order to evaluate the underlying mechanisms for these abnormalities, TH transport and metabolism have been intensively studied in different tissues of Mct8 ko mice. Here, we summarize the observed changes within the hypothalamus-pituitary-thyroid axis that result in altered TH production and secretion. Although analysis of Mct8 ko mice has greatly expanded our knowledge, many open questions still remain to be addressed in order to define the tissue- and cell-specific role of this important TH transporter.
Introduction
The availability of sufficient amounts of thyroid hormone (TH) is a prerequisite for almost all physiological processes and normal tissue function. In particular, TH is essential for a normal maturation of the central nervous system (CNS). TH deprivation during critical stages of brain development will affect events such as neuronal differentiation, synaptogenesis and myelination and, therefore, can lead to irreversible brain damage [1,2,3,4].
In order to unravel the molecular actions by which TH modulates tissue function and controls brain development, TH receptors have been extensively studied and excellent reviews about TRs have been published [5,6,7,8]. Another very active field of research is to delineate the role of deiodinases (D1, D2, D3) that can activate and inactivate TH by outer- and inner-ring deiodination, respectively. These deiodinases represent important determinants in regulating systemic as well as local TH concentrations [9,10,11,12]. Most of the circulating iodothyronine T3 is not produced by the thyroid itself but generated by deiodinases D1 and D2 expressed in peripheral tissues and in the brain, respectively. Deiodinase type 3 catalyzes only the inactivation of TH and is in particular strongly expressed in the CNS and in fetal tissues.
For a long time the common assumption persisted that TH can pass the phospholipid bilayer simply by passive diffusion due to the lipophilic nature of TH. However, in the last decade it has become clear that influx and efflux of TH are carrier-mediated events [13,14,15,16]. Up to now, numerous transporters have been identified that are more or less specific in transporting iodothyronines in and out of cells, namely the Na+-taurocholate cotransporting polypeptide, members of the Na+-independent organic anion transporting polypeptide (OATP) family, the heterodimeric L-type amino acid transporters Lat1 and Lat2 as well as the monocarboxylate transporters Mct10 and Mct8.
Of all these transporter candidates, Mct8 has attracted a great deal of attention as it shows a highly restricted substrate specificity [17,18]. Both human and rat Mct8 transport iodothyronines very efficiently in a bidirectional manner, but they do not accept any other substrate tested so far. In comparison, Mct10, as another member of the monocarboxylate transporter family, is similarly effective in mediating the transport of TH [19]. However, in contrast to Mct8, Mct10 also transports aromatic amino acids.
The human MCT8 gene (SLC16A2) is located on the X chromosome (Xq13.2) and was initially cloned by Lafrenière et al. [20] in 1994. It contains 6 exons and 5 introns encoding a 60-kDa membrane-spanning protein with 12 putative transmembrane domains and both, the N- and the C-terminal domains, are located intracellularly [20,21]. In humans, MCT8 mRNA was found to be highly expressed in liver, kidney, heart, placenta, lung, thyroid as well as in brain and pituitary [22]. Here, we will summarize the consequences of Mct8 deficiency in humans and mice with a special focus on the hypothalamus-pituitary-thyroid axis.
Phenotype of MCT8 Patients
The physiological significance of Mct8 as a transporter critical for TH homeostasis and the supply of TH to the developing brain was underscored by the identification of patients who carry inactivating mutations or deletions in the MCT8 gene (SLC16A2). Since the MCT8 gene is encoded on the X chromosome (Xq13.2) the disease was described as an X-linked psychomotor retardation syndrome [23,24]. Subsequently, mutations in the MCT8 gene were discovered to be associated with the long known Allan-Herndon-Dudley syndrome (AHDS) [25]. Following these initial descriptions, mutations in more than 50 families have been described so far [26]. With the ongoing screenings initiated, the number of patients diagnosed with a defect in MCT8 is expected to even further increase in the upcoming years.
All patients with an inactivating MCT8 mutation suffer from a unique syndrome. They show serious mental deficits, congenital hypotonia, spastic or dystonic quadriplegia, seizures, as well as muscle hypoplasia, generalized muscle weakness with poor head control. Many of them are not able to sit, stand or walk independently, and do not develop any speech [25,27,28]. Interestingly, the severity of the syndrome seems to correlate with the impact of the respective mutation on the TH transport activity of MCT8. Mutations in MCT8 that still allow residual TH transport are associated with a more advanced psychomotor development, whereas mutations that lead to a complete loss of function are linked to more dramatic forms of neurological impairments [26,29].
Information about the cellular damage in the CNS of these patients is still rather limited. Brain magnetic resonance imaging studies of young MCT8 patients (<2 years) revealed that Mct8 deficiency gives rise to anomalous myelination as well as brain atrophy [30,31]. In addition, MCT8 mutations have been reported in patients affected by hypomyelinating leukodystrophies initially diagnosed with Pelizeus-Merzbacher-like disease [32]. A delayed myelination would also be a hallmark of patients that suffer from insufficient TH supply during critical stages of brain development. Consequently, a hypothyroid situation in the brain might be envisaged for patients with MCT8 mutations.
A second hallmark of the ‘MCT8 disease’ are very unusual TH parameters [21,33]. All patients show strongly increased serum T3 levels, while T4 and rT3 concentrations are rather low. TSH values are in the normal range or even slightly elevated. These findings clearly underline the physiological significance of MCT8 for TH transport in vivo, although, at least at first glance, the pathogenic mechanisms from which these TH abnormalities arise are not obvious.
Phenotype of Mct8 Knockout Mice
In order to get further insights into the mechanisms underlying the neurological and endocrine symptoms observed in MCT8 patients, two different Mct8-deficient mouse models have been generated and intensively analyzed [34,35]. Mct8 knockout (ko) mice fully reproduce the TH abnormalities found in the patients and exhibit highly increased T3 (twofold) and reduced T4 (to 34%) and rT3 values resulting in a strikingly increased T3/T4 ratio (sixfold). However, they completely lack any neurological or locomotor impairment and display a normal brain morphology [36], suggesting that Mct8 may be of minor importance for proper development of the murine brain.
This was a rather unexpected finding since in the mouse CNS, Mct8 is highly expressed in TH-sensitive neuronal populations such as in the cerebral and cerebellar cortex as well as in the hippocampus and striatum where it has been speculated to mediate neuronal T3 uptake [37]. Moreover, Mct8 was also localized in choroid plexus structures and in brain capillary endothelial cells where it may participate in the transport of TH via the blood-brain barrier (BBB) and/or blood-CSF barrier [38]. Indeed, in vivo transport studies revealed a strongly diminished uptake of T3 into the brain of Mct8 ko mice. In contrast, the transport of T4 was only mildly affected [35]. Thus, Mct8 is critically involved in the passage of T3 into the brain, whereas at least one additional T4 transporter must exist that can compensate for the absence of Mct8 in the mouse but not in the human brain. Such a candidate is represented by Oatp1c1 that preferentially transports T4 [39,40]. Indeed, a first analysis of Oatp1c1-deficient mice points to a role of this transporter in the uptake of T4 at the BBB as Oatp1c1 ko animals showed a reduced brain T4 content despite normal Mct8 expression at the BBB and normal TH levels in the circulation [41].
The significance of Mct8 in neuronal T3 transport is less clear. Due to the low T4 concentrations in the CNS of Mct8 ko mice, a strong compensatory upregulation of D2 activity together with a decreased expression of D3 could be detected indicating that the local production of T3 within the brain is strongly induced and TH inactivation by inner-ring deiodination is downregulated [34,35]. Apparently, this increase in T4 to T3 conversion by D2 is effectual to provide most of the neuronal cells with sufficient amounts of T3 and, hence, serious brain damages can be prevented. Some neurons in the Mct8 ko brain, however, show a reduced expression of T3-sensitive target genes like neurogranin (RC3) in the striatum and hairless in the cerebral cortex [35,42]. Currently, it is unknown whether these mild alterations reflect inadequate local T3 production or partially impaired neuronal T3 uptake due to the missing of Mct8. Future studies using conditional Mct8 mouse mutants will hopefully help to clarify this question.
In mice, Mct8 is not the only TH transporter localized to neurons, and species differences between mice and men with respect to the cell-specific TH transporter repertoire have undoubtedly been demonstrated. As one example, the L-type amino acid transporter Lat2 that can act as a TH transporter as well is present in murine neurons and glia cells, whereas in the human brain its expression is restricted to microglia cells [36,43]. Thus, as another hypothesis, a possible compensation for the lack of Mct8 by Lat2 has been put forward in order to explain the lack of any neurological damage in Mct8 ko mice. Again, future mouse studies using Mct8/Lat2 double ko (dko) mice are expected to respond to this question.
Role of Mct8 in the Hypothalamus
In contrast to the rather mild hypothyroid situation in the brain of Mct8-deficient animals, one specific subset of neurons appears to be more prominently affected by the absence of Mct8, namely the hypophysiotropic TRH-producing cells in the hypothalamic paraventricular nucleus (PVN). In situ hybridization studies revealed a strong upregulation of TRH mRNA expression in these TH-sensitive neurons indicating a pronounced hypothyroidal state [35]. This difference may have several reasons. For example, the uptake of T3 into these neurons might be restricted due to the absence of Mct8 in these cells. However, peripheral application of pharmacological doses of T4 are sensed by the TRH neurons and resulted in a downregulation of TRH expression. Thus, T3 import into PVN cells must still be possible in the absence of Mct8 and the hypothyroidal state may be rather due to an insufficient local T3 supply. In this respect, tanycytes that are specialized glia cells lining the third ventricle seem to exert an important function. With their long processes they are able to make contact with the axonal endings of TRHergic fibers in the median eminence [44]. Under normal conditions, tanycytes express high levels of D2 as well as of Mct8 [36,37,45]. Based on their unique features, it is tempting to speculate that they may serve a special function within the negative feedback loop by providing the TRH neurons with T3, a function that may be partially impeded when Mct8 is missing. Consecutively, TRHergic neurons may secrete elevated amounts of TRH that in turn can affect pituitary function.
Such changes in hypothalamic TH sensing are most likely not specific for the mouse brain but may also occur in a similar manner in the human MCT8-deficient brain. In contrast to other areas of the human CNS, MCT8 distribution, carefully mapped in the human hypothalamus, revealed the localization of the transporter in PVN neurons as well as in glial cells [46,47,48]. Thus, it is tempting to speculate that patients with inactive MCT8 may also exhibit an increased hypothalamic TRH secretion.
Role of Mct8 in the Pituitary
One of the most enigmatic findings concerns the role of Mct8 in the pituitary. Both in the human and in the mouse anterior lobe, Mct8 is not expressed in thyrotrophs as one might assume but it is restricted to folliculostellate cells [48,49]. In mice, Mct8-specific in situ hybridization signals were also found in pituicytes of the posterior lobe and in a thin line of cells at the border of the anterior and intermediate loop (fig. 1). The function of Mct8 in these non-hormone-producing cells is completely unclear. Determination of TSH mRNA levels in the Mct8 ko mouse models revealed slightly elevated transcript levels that also fit to the increased serum TSH values found in these animals indicating that at least the pituitary thyrotrophs are in a mild hypothyroid state [34,50]. This assumption is supported by moderately increased activities of the enzyme D2[35] that in mice are localized in TSH-producing cells [51,52]. That thyrotrophs do indeed not sense appropriately the high circulating T3 levels could also be confirmed by TSH suppression tests [34,35]. When Mct8-deficient mice were rendered hypothyroid by mercaptoimidazole treatment, only the application of high T3 concentrations was successful in suppressing endogenous TSH production. Not surprisingly, hypothalamic TRH expression did not show any response towards the T3 treatment due to the impaired T3 passage into the CNS. A similar pituitary resistance to TH has also been observed in patients with MCT8 mutations [53]. Altogether, in the absence of Mct8, the pituitary is unable to integrate the high T3 serum levels adequately, but the underlying mechanism of this resistance remains mysterious and requires further investigations.
Consequences of Mct8 deficiency on TH tissue concentrations, metabolism and transport in mice. Images illustrate Mct8 expression in different tissues as revealed by β-galactosidase immunoreactivity (hypothalamus, CNS), and radioactive in situ hybridization (pituitary, thyroid, liver, kidneys), respectively. a In mice, Mct8 is highly expressed in the PVN of the hypothalamus, in the anterior as well as in the posterior pituitary and in follicular epithelial cells of the thyroid gland. Absence of Mct8 results in increased hypothalamic TRH expression, a moderate increase in pituitary TSH mRNA levels and a strong elevation of free and thyroglobulin bound T3 and T4 content in the thyroid gland. b A characteristic hallmark of Mct8 deficiency are abnormal serum TH levels with elevated T3 and reduced T4. In the CNS, Mct8 is highly expressed in neurons as demonstrated for the hippocampal area (Hip), in endothelial cells of the BBB as well as in tanycytes (T) that represent specialized glia cells lining the third ventricle (3V) and are in contact with the median eminence (ME). Mct8 ko mice exhibit a strongly diminished uptake of T3 into the brain whereas transport of T4 is not impeded. Consequently, the brain is in a hypothyroid state with increased D2 and decreased D3 activities as well as reduced T3 and T4 brain content. Liver and kidneys are also affected by Mct8 deficiency and show highly elevated D1 expression and strongly induced T3 tissue content. In the liver, T4 concentrations are similar to those observed in wild-type littermates (=) indicating that Mct8 deficiency may result in a moderate retention of T4 in the liver. In the kidneys, transport studies revealed a highly stimulated uptake of both T3 and T4 that in turn leads to an accumulation of TH in this tissue. As a result, liver and kidneys of Mct8 ko mice are in a thyrotoxic state.
Citation: European Thyroid Journal 1, 2; 10.1159/000339474
Role of Mct8 in the Thyroid Gland
In addition to the hypothalamus and pituitary, the thyroid gland appears to be affected by the lack of Mct8 as well. Compared to other TH transporters in wild-type mice, Mct8 is highly expressed in follicular cells of the thyroid gland [50,54,55]. Based on its basolateral localization it is tempting to speculate that Mct8 may be involved in TH efflux, and the analysis of Mct8-deficient animals strongly supports this hypothesis. Moreover, due to the elevated serum TSH levels, TH production may be constantly stimulated that in turn can influence thyroid morphology.
In fact, gross histological examination revealed an enlarged thyroid gland in Mct8 ko mice. Quantification of thyroid follicle parameters demonstrated the presence of bigger follicles in the absence of Mct8, a phenotype that even progresses with age [50,54,55]. Furthermore, starting from the age of 6 months, papillary structures in the thyroid gland became evident [50]. At the age of 12 months, more than 80% of Mct8 ko mice showed pathological abnormalities. In 1 patient with a MCT8 mutation who underwent thyroidectomy, follicular irregularities were diagnosed as well [50]. So far, the underlying mechanisms are rather unknown, and it also remains to be evaluated whether the age-dependent development of papillary thyroid carcinoma is a general hallmark of Mct8 deficiency.
Determination of the thyroidal TH content revealed significantly increased Tg bound and free T3 and T4 concentrations in the thyroids of adult Mct8 ko mice [54,55,56]. These alterations may be a consequence of the elevated serum TSH levels. In fact, our analysis of Mct8/Trhr1 dko mice that are characterized by a reduction in TSH activity demonstrated strongly reduced free and Tg-bound TH content in the thyroid gland compared to the single Mct8 ko mice. However, independent of the TH content in the gland, T4 secretion is impaired in the absence of Mct8 as shown by TSH stimulation tests using Mct8 ko and Mct8/Trhr1 dko mice [55]. Moreover, Mct8 ko mice that were set on a 2-week low-iodine diet and then injected with 125I, exhibited a reduced rate of radioiodine clearance from the thyroid gland and a reduced appearance of labeled iodothyronine in the serum [54], an observation that further supports a role of Mct8 in TH secretion.
In addition to the decrease in T4 export, we observed a rather surprising finding with respect to the release of T3. Following TSH stimulation, both Mct8 ko mice as well as Mct8/Trhr1 dko mice displayed an enhanced thyroidal efflux of T3[55]. We speculated that due to a partial retention of T4 in thyrocytes, more T4 is accessible to thyroidal D1. This may lead to an increased intrathyroidal T4 to T3 turnover and consequently to an altered ratio of TH released from the gland. Such a shift would be further amplified peripherally by D1 in hepatocytes and kidney cells that converts even more T4 to T3. According to this hypothesis, alterations in thyroidal TH secretion would represent an important mechanism that contributes to the generation of the abnormal TH levels. A powerful approach to test this hypothesis would be the tissue-specific inactivation of Mct8 in the thyroid gland by taking advantage of conditional Mct8 mutant mice.
That the thyroid gland may contribute at least partially to the increase in serum T3 could be also shown by a more indirect approach. By crossing Mct8 ko mice with Pax8 ko mice, we were able to produce animals that not only lack Mct8 but also do not develop a functional thyroid gland [57]. These athyroid mice do not produce any TH endogenously and are therefore perfectly suited for TH substitution experiments. Indeed, daily injection of Pax8 ko mice with 20 ng/g b.w. T4 was sufficient to produce T3 and T4 serum levels similar to those found in wild-type littermates that have a functional thyroid gland [58]. When the same dose of T4 was applied to Mct8/Pax8 dko mice during the first 3 weeks of life, serum T3 concentrations were similar to that detected in control animals as well [55]. Thus, we concluded that in Mct8 deficiency normal circulating T3 levels can be achieved by T4 replacement therapy as long as the influence of the hypothalamus-pituitary-thyroid axis is abolished.
Despite the fact that T3 was normalized in T4-treated Mct8/Pax8 dko mice, serum T4 values were still strikingly low. This observation indicates that rather extrathyroidal mechanisms must play a role in minimizing circulating T4, whereas an impaired thyroidal T4 secretion contributes only to a minor extent to this phenotype but initiates the imbalances reinforced by a vicious circle. This situation does not seem to be specific for mice but also holds true for humans as decreased serum T4 has been observed in 1 patient who underwent thyroidectomy and was subsequently substituted with T4[50].
Where does T4 disappear from the circulation? We considered a renal contribution since Mct8 is highly expressed at the basolateral site of the proximal tubule cells. Moreover, Mct8 ko mice show an increased renal uptake of T3 and T4 suggesting that Mct8 may primarily act as an TH export system. As a consequence, kidney TH content and even more so urinary TH concentrations are pronouncedly elevated [59]. In addition, D1 activity in the kidneys is strongly induced indicating a thyrotoxic state of this tissue. Why renal TH transport is enhanced in the absence of Mct8 is another important question to be addressed in further studies. It remains to be investigated to which extent Mct8 plays a role in the hepatic TH efflux as well since recent data suggest an impairment in hepatic T4 release [56]. Such changes may also contribute to the hyperthyroidal state of the liver that has been described in the Mct8 ko mouse. Recent studies have demonstrated that alterations in D1 activities are involved in the generation of the abnormal serum profile as Mct8/D1 dko mice show a partial normalization in serum TH values. Although a major impact of increased hepatic D1 activities has been discussed, final proof for this assumption is still missing since in addition to the liver, D1 is also present in the kidneys and in the thyroid [56].
Conclusion and Outlook
Overall, Mct8 deficiency results in robust tissue-specific alterations in TH transport, metabolism and action. The analysis of Mct8 ko mice has significantly expanded our knowledge how different tissues are affected by Mct8 deficiency. A simplified cartoon illustrating the alterations described so far is depicted in figure 1. We speculate that many of these alterations take place in patients as well. As one example, patients show elevated levels of sex hormone-binding globulin, an indicator for liver thyrotoxicosis [60,61]. However, the studies of Mct8 ko mice have also revealed the limitations of this animal model. Due the vast array of changes caused by the ubiquitous inactivation of Mct8, it is almost impossible to define the exact cell-specific function of the transporter. In this respect, we await the generation and analysis of tissue-specific Mct8 mutant mice that will shed further light on the function of this unique TH transporter.
Disclosure Statement
The authors have no conflicts of interest to disclose.
Footnotes
verified
References
- 2↑
Morreale de Escobar G, Obregon MJ, Escobar del Rey F: Role of thyroid hormone during early brain development. Eur J Endocrinol 2004;151(suppl 3):U25–U37.
- 4↑
Nunez J, Celi FS, Ng L, Forrest D: Multigenic control of thyroid hormone functions in the nervous system. Mol Cell Endocrinol 2008;287:1–12.
- 5↑
Bassett JH, Harvey CB, Williams GR: Mechanisms of thyroid hormone receptor-specific nuclear and extranuclear actions. Mol Cell Endocrinol 2003;213:1–11.
- 6↑
Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels H, Scanlan TS, Vennstrom B, Samarut J: International union of pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev 2006;58:705–711.
- 7↑
Bernal J: Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007;3:249–259.
- 8↑
Cheng SY, Leonard JL, Davis PJ: Molecular aspects of thyroid hormone actions. Endocr Rev 2010;31:139–170.
- 9↑
Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR: Biochemistry, cellular and molecular biology, and physiological roles of the iodothyrodine selenodiodinases. Endocr Rev 2002;23:38–89.
- 10↑
Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeold A, Bianco AC: Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008;29:898–938.
- 11↑
Dentice M, Salvatore D: Deiodinases: the balance of thyroid hormone: local impact of thyroid hormone inactivation. J Endocrinol 2011;209:273–282.
- 12↑
Williams GR, Bassett JH: Deiodinases: the balance of thyroid hormone. Local control of thyroid hormone action: role of type 2 deiodinase. J Endocrinol 2011;209:261–272.
- 13↑
Friesema EC, Jansen J, Milici C, Visser TJ: Thyroid hormone transporters. Vitam Horm 2005;70:137–167.
- 14↑
Visser WE, Friesema EC, Jansen J, Visser TJ: Thyroid hormone transport in and out of cells. Trends Endocrinol Metab 2008;19:50–56.
- 15↑
Heuer H, Visser TJ: Pathophysiological importance of thyroid hormone transporters. Endocrinology 2009;150:1078–1083.
- 16↑
Visser WE, Friesema EC, Visser TJ: Thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol 2011;25:1–14.
- 17↑
Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ: Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 2003;278:40128–40135.
- 18↑
Kinne A, Kleinau G, Hoefig CS, Gruters A, Kohrle J, Krause G, Schweizer U: Essential molecular determinants for thyroid hormone transport and first structural implications for monocarboxylate transporter 8. J Biol Chem 2010;285:28054–28063.
- 19↑
Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ: Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 2008;22:1357–1369.
- 20↑
Lafrenière R, Carrel L, Willard HJ: A novel transmembrane transporter encoded by the Xpct gene in Xq13.2. Hum Mol Genet 1994;3:1133–1139.
- 21↑
Friesema EC, Jansen J, Heuer H, Trajkovic M, Bauer K, Visser TJ: Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nat Clin Pract Endocrinol Metab 2006;2:512–523.
- 22↑
Price NT, Jackson VN, Halestrap AP: Cloning and sequencing of four new mammalian monocarboxylate transporter (Mct) homologues confirms the existence of a transporter family with an ancient past. Biochem J 1998;329:321–328.
- 23↑
Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S: A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004;74:168–175.
- 24↑
Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ: Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004;364:1435–1437.
- 25↑
Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE: Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet 2005;77:41–53.
- 26↑
Friesema EC, Visser WE, Visser TJ: Genetics and phenomics of thyroid hormone transport by MCT8. Mol Cell Endocrinol 201030;322:107–113.
- 27↑
Brockmann K, Dumitrescu AM, Best TT, Hanefeld F, Refetoff S: X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. J Neurol 2005;252:663–666.
- 28↑
Holden KR, Zuniga OF, May MM, Su H, Molinero MR, Rogers RC, Schwartz CE: X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype. J Child Neurol 2005;20:852–857.
- 29↑
Jansen J, Friesema EC, Kester MH, Schwartz CE, Visser TJ: Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8. Endocrinology 2008;149:2184–2190.
- 30↑
Namba N, Etani Y, Kitaoka T, Nakamoto Y, Nakacho M, Bessho K, Miyoshi Y, Mushiake S, Mohri I, Arai H, Taniike M, Ozono K: Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter. Eur J Pediatr 2008;167:785–791.
- 31↑
Sijens PE, Rodiger LA, Meiners LC, Lunsing RJ: 1h magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency. J Clin Endocrinol Metab 2008;93:1854–1859.
- 32↑
Vaurs-Barriere C, Deville M, Sarret C, Giraud G, Des Portes V, Prats-Vinas JM, De Michele G, Dan B, Brady AF, Boespflug-Tanguy O, Touraine R: Pelizaeus-Merzbacher-like disease presentation of MCT8 mutated male subjects. Ann Neurol 2009;65:114–118.
- 33↑
Refetoff S, Dumitrescu AM: Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007;21:277–305.
- 34↑
Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S: Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter 8-deficient mice. Endocrinology 2006;147:4036–4043.
- 35↑
Trajkovic M, Visser TJ, Mittag J, Horn S, Lukas J, Darras VM, Raivich G, Bauer K, Heuer H: Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 2007;117:627–635.
- 36↑
Wirth EK, Roth S, Blechschmidt C, Holter SM, Becker L, Racz I, Zimmer A, Klopstock T, Gailus-Durner V, Fuchs H, Wurst W, Naumann T, Brauer A, de Angelis MH, Kohrle J, Gruters A, Schweizer U: Neuronal 3′,3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome. J Neurosci 2009;29:9439–9449.
- 37↑
Heuer H, Maier MK, Iden S, Mittag J, Friesema EC, Visser TJ, Bauer K: The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology 2005;146:1701–1706.
- 38↑
Ceballos A, Belinchon MM, Sanchez-Mendoza E, Grijota-Martinez C, Dumitrescu AM, Refetoff S, Morte B, Bernal J: Importance of monocarboxylate transporter 8 for the blood-brain barrier-dependent availability of 3,5,3′-triiodo-L-thyronine. Endocrinology 2009;150:2491–2496.
- 39↑
Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y: Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain-barrier. J Biol Chem 2003;278:43489–43495.
- 40↑
Roberts LM, Woodford K, Zhou M, Black DS, Haggerty JE, Tate EH, Grindstaff KK, Mengesha W, Raman C, Zerangue N: Expression of the thyroid hormone transporters Mct8 (SLC16A2) and Oatp14 (SLCO1C1) at the blood-brain barrier. Endocrinology 2008;149:6251–6261.
- 41↑
Mayerl S, Visser TJ, Darras VM, Horn S, Heuer H: Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain. Endocrinology 2012;153:1528–1537.
- 42↑
Morte B, Ceballos A, Diez D, Grijota-Martinez C, Dumitrescu AM, Di Cosmo C, Galton VA, Refetoff S, Bernal J: Thyroid hormone-regulated mouse cerebral cortex genes are differentially dependent on the source of the hormone: a study in monocarboxylate transporter-8- and deiodinase-2-deficient mice. Endocrinology 2010;151:2381–2387.
- 43↑
Braun D, Kinne A, Brauer AU, Sapin R, Klein MO, Kohrle J, Wirth EK, Schweizer U: Developmental and cell type-specific expression of thyroid hormone transporters in the mouse brain and in primary brain cells. Glia 2011;59:463–471.
- 44↑
Sanchez E, Vargas MA, Singru PS, Pascual I, Romero F, Fekete C, Charli JL, Lechan RM: Tanycyte pyroglutamyl peptidase II contributes to regulation of the hypothalamic-pituitary-thyroid axis through glial-axonal associations in the median eminence. Endocrinology 2009;150:2283–2291.
- 45↑
Tu HM, Kim SW, Salvatore D, Bartha T, Legradi G, Larsen PR, Lechan RM: Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone. Endocrinology 1997;138:3359–3368.
- 46↑
Alkemade A, Friesema EC, Unmehopa UA, Fabriek BO, Kuiper GG, Leonard JL, Wiersinga WM, Swaab DF, Visser TJ, Fliers E: Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus. J Clin Endocrinol Metab 2005;90:4322–4334.
- 47↑
Fliers E, Alkemade A, Wiersinga WM, Swaab DF: Hypothalamic thyroid hormone feedback in health and disease. Prog Brain Res 2006;153:189–207.
- 48↑
Fliers E, Unmehopa UA, Alkemade A: Functional neuroanatomy of thyroid hormone feedback in the human hypothalamus and pituitary gland. Mol Cell Endocrinol 2006;251:1–8.
- 49↑
Alkemade A, Friesema EC, Kuiper GG, Wiersinga WM, Swaab DF, Visser TJ, Fliers E: Novel neuroanatomical pathways for thyroid hormone action in the human anterior pituitary. Eur J Endocrinol 2006;154:491–500.
- 50↑
Wirth EK, Sheu SY, Chiu-Ugalde J, Sapin R, Klein MO, Mossbrugger I, Quintanilla-Martinez L, de Angelis MH, Krude H, Riebel T, Rothe K, Kohrle J, Schmid KW, Schweizer U, Gruters A: Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy. Eur J Endocrinol 2011;165:555–561.
- 51↑
Christoffolete MA, Ribeiro R, Singru P, Fekete C, da Silva WS, Gordon DF, Huang SA, Crescenzi A, Harney JW, Ridgway EC, Larsen PR, Lechan RM, Bianco AC: Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism. Endocrinology 2006;147:1735–1743.
- 52↑
Mittag J, Friedrichsen S, Strube A, Heuer H, Bauer K: Analysis of hypertrophic thyrotrophs in pituitaries of athyroid Pax8–/– mice. Endocrinology 2009;150:4443–4449.
- 53↑
Biebermann H, Ambrugger P, Tarnow P, Von Moers A, Schweizer U, Grueters A: Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8. Eur J Endocrinol 2005;153:359–366.
- 54↑
Di Cosmo C, Liao XH, Dumitrescu AM, Philp NJ, Weiss RE, Refetoff S: Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion. J Clin Invest 2010;120:3377–3388.
- 55↑
Trajkovic-Arsic M, Muller J, Darras VM, Groba C, Lee S, Weih D, Bauer K, Visser TJ, Heuer H: Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice. Endocrinology 2010;151:5053–5062.
- 56↑
Liao XH, Di Cosmo C, Dumitrescu AM, Hernandez A, Van Sande J, St Germain DL, Weiss RE, Galton VA, Refetoff S: Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes. Endocrinology 2011;152:1180–1191.
- 57↑
Mansouri A, Chowdhury K, Gruss P: Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 1998;19:87–90.
- 58↑
Friedrichsen S, Christ S, Heuer H, Schafer MK, Mansouri A, Bauer K, Visser TJ: Regulation of iodothyronine deiodinases in the Pax8–/– mouse model of congenital hypothyroidism. Endocrinology 2003;144:777–784.
- 59↑
Trajkovic-Arsic M, Visser TJ, Darras VM, Friesema EC, Schlott B, Mittag J, Bauer K, Heuer H: Consequences of monocarboxylate transporter 8 deficiency for renal transport and metabolism of thyroid hormones in mice. Endocrinology 2010;151:802–809.
- 60↑
Herzovich V, Vaiani E, Marino R, Dratler G, Lazzati JM, Tilitzky S, Ramirez P, Iorcansky S, Rivarola MA, Belgorosky A: Unexpected peripheral markers of thyroid function in a patient with a novel mutation of the Mct8 thyroid hormone transporter gene. Horm Res 2007;67:1–6.
- 61↑
Wemeau JL, Pigeyre M, Proust-Lemoine E, d’Herbomez M, Gottrand F, Jansen J, Visser TJ, Ladsous M: Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8. J Clin Endocrinol Metab 2008;93:2084–2088.
