The Significance of Thyroid Hormone Transporters in the Brain
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内分泌学杂志 2005年第4期
Instituto de Investigaciones Biomédicas 28029 Madrid, Spain
Address all correspondence and requests for reprints to: Prof. Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain.
The developing brain is an important target of thyroid hormones. A complex regulatory network involving transfer of thyroid hormones through the brain barriers, interactions between neurons and glial cells, and deiodinase expression, works to deliver the appropriate amount of T3 to the nuclear receptors. The data provided by Heuer et al. (1) in this issue indicates that specific thyroid hormone transporters may also be an essential part of this regulatory system.
Thyroid hormones influence brain development from about the end of the first trimester of fetal life. The human fetal brain expresses nuclear T3 receptors at least from the 10th week of gestation, and receptor concentration increases 10-fold during the second trimester in brain and other tissues (2). T4 is present in brain and other tissues, such as liver, kidney, and lung, but T3 is detectable only in brain, at concentrations that result in an occupancy of brain T3 receptors around 25%. The source of T4 reaching the fetal brain up to midgestation is mostly of maternal origin (3). Both T4 and T3 cross the placenta and reach the fetal organs, but only T4 appears to cross the fetal blood-brain barrier. Thus, the administration of T3 by constant infusion to pregnant rat dams increased T3 concentrations in all maternal and fetal tissues except the fetal brain (4). In contrast, the administration of T4 increased T3 content in fetal brain as well as in other tissues. There was also a very important difference between the brain and the rest of the tissues. When increasing amounts of T4 were administered to pregnant dams maintained on methimazole, normal concentrations of T3 in the fetal brain were kept over a much wider range of T4 doses than in other tissues.
In adult rats, both T4 and T3 reach the brain from blood, but it was estimated that as much as 80% of the T3 bound to the nuclear receptors was produced locally by type 2 deiodinase (D2) activity (5). As in fetal brain, when either T4 or T3 was administered to hypothyroid rats, the T3 content of the brain was maintained within control values only by T4, but not by T3, infusion (6). Homeostasis of T3 within the brain is maintained within narrow limits by a complex mechanism involving D2 and D3. Several years ago we reported that D2 was predominantly expressed in glial cells of two types, tanycytes and astrocytes (7) (Fig. 1). Tanycytes, in which expression of D2 was also reported by Tu et al. (8), are specialized ependymal cells lining the third ventricle and extending processes to the adjacent hypothalamus and the median eminence. The T3 generated by these cells from cerebrospinal T4 could play a role in TRH-TSH regulation. On the other hand, expression of D2 in the astrocytes suggested to us the existence of interplay between astrocytes and neurons on T3 homeostasis similar to the metabolic coupling between the two cells concerning the glutamate-glutamine cycle or glucose use (9). Astrocytes would produce T3 for neuronal use. As an additional control of neuronal T3 concentration, D3, which degrades T3 to the inactive metabolite diiodothyronine, is expressed in neurons. In this issue, Heuer et al. (1) confirm expression of D2 in the astrocytes and suggest important roles in T3 homeostasis for recently characterized thyroid hormone transporters (Fig. 1).
FIG. 1. Thyroid hormones are transported through the blood-brain barrier (OATP) or the blood-CSF barrier (OATP and MCT8). In the astrocytes and tanycytes T4 is converted to T3 which then enters the neurons through MCT8. In the neurons both T4 and T3 are degraded by D3. T3 from the tanycytes may reach the portal vessels in the median eminence. Other transporters may be present on the astrocyte or tanycyte membranes. In most cases the transport could be bidirectional, although only one direction is shown.
The entry of thyroid hormones into the cells has for a long time been assumed to be by passive diffusion, because thyroid hormones are lipophilic molecules and as such could easily enter the membrane lipid bilayer. Experiments in vivo hardly gave any hint of a saturable process, as was, for example, the binding of T3 to the nucleus, an observation that facilitated the discovery of nuclear receptors. However, in isolated hepatocytes and other cell types, the demonstration of relatively high-affinity sites for both T4 and T3, and the inhibition of cellular uptake by metabolic inhibitors, amino acids, and other chemicals, gave evidence for the physiological significance of thyroid hormone transporters (10). Several molecular entities have been identified as transporters for thyroid hormone (11). They belong to three main families: the organic anion-transporting polypeptides (OATP), the L-amino acid transporters, and the monocarboxylate anion transporters (MCT).
Among the many members of the OATP family, human OATP-F (12) and rat Oatp14 (13) are preferentially expressed in brain. The Oatp14 protein is localized in the border of brain capillary endothelial cells and in the choroid plexus. OATP-F/Oatp14 transports T4 and rT3 much more efficiently than T3, and might be involved in the transport of T4 through the blood-brain barrier and through the choroid plexus, and also in rT3 clearance. The blood-brain barrier is the route by which thyroid hormone is preferentially distributed throughout the brain, and this transporter could facilitate uptake of T4 by the astrocytes. Transfer of thyroid hormone through the choroid plexus achieves only limited diffusion to the brain parenchyma after passage to the cerebrospinal fluid but would allow uptake of T4 by tanycytes and subsequent T3 generation in these cells.
The MCT family comprises up to 14 members, some of which are involved in the transport of important substrates for the brain such as lactate and pyruvate. MCT8 has been shown to act as a specific transporter for T4 and T3 and displays slightly higher affinity for T3 (14). Heuer et al. (1) have also studied the regional expression of MCT8 mRNA. In addition to high expression levels in the choroid plexus, they found that MCT8 is expressed in neurons of the neocortex, hippocampus, basal ganglia, amygdala, hypothalamus, and the Purkinje cells of the cerebellum, all regions known to be sensitive to thyroid hormones (15). Expression of MCT8 in neurons suggests that neuronal uptake of the T3 produced in astrocytes is facilitated by this transporter.
The physiological significance of MCT8 as a transporter for thyroid hormone is supported by the finding of mutations in humans by Dumitrescu et al. (16) and Friesema et al. (17). The syndrome affects children from an early age and consists of severe developmental delay and neurological damage together with an unusually altered pattern of thyroid hormone levels in blood. The patients presented low total and free T4, high total and free T3, and low rT3. TSH was moderately elevated in two of the patients and normal or slightly elevated in the other five. Inactivating mutations of the MCT8 transporter could result in the altered thyroid hormone levels. In vitro uptake of T4 and T3 by fibroblasts isolated from affected males was strongly reduced, and intracellular D2 was increased 6- to 8-fold (17). It is thus hypothesized that the resulting increase in intracellularly generated T3 accumulates in blood because of its poor reuptake into cells. In addition, deficient uptake of T4 and T3 by neurons could reduce degradation by neuronal D3 to rT3 and diiodothyronine, respectively, with increased T3 and decreased rT3. The brain and skin are predominant sites of D3 expression, but their contribution to T3 degradation and to blood rT3 is difficult to estimate (18).
The neurological syndrome caused by MCT8 mutations consists of developmental delays, rotary nystagmus, severe proximal hypotonia with poor head control, spastic quadriplegia, dystonic movements, and impaired gaze and hearing. More recently, a syndrome of paroxysmal dyskinesia has been recognized by Brockmann et al. (19) in the two patients originally described by Dumitrescu et al. (16). The whole clinical picture is so severe that it is pertinent to ask the question of whether the impaired uptake and action of thyroid hormone on neurons could cause such a syndrome. The neurological disorder of endemic cretinism (neurological cretinism) consists of variable degrees of neuromotor affectation with proximal limb girdle spasticity and rigidity, more often affecting the lower extremities, extrapyramidal disorders of rigidity and bradykinesia, deaf-mutism, strabismus, dysarthria, and mental deficiency (20). Epidemiological and physiopathological considerations indicate that this syndrome is most probably a result of lack of thyroid hormone during fetal development, especially before midgestation. This is the period of neuroblast proliferation and maturation of the basal ganglia and cerebral cortex. In the postmortem examination of the maternal uncle of one of the patients, also probably affected, loss of neurons in the cerebral cortex, basal ganglia, and cerebellum was found (16). As mentioned above, the second trimester is also the period when thyroid hormone receptors increase in concentration in the brain. If MCT8 is needed at this stage of development for T3 entry into neurons, mutations of the transporter could also interfere with T3-dependent developmental processes. Knowledge of the ontogenetic patterns of MCT8 in the human fetal brain would certainly be helpful. On the other hand, there is also the possibility that MCT8 mutations interfere with transport of other substrates for brain metabolism that could be even more important than T3 in determining the severity and outcome of the syndrome. Other members of the family transport metabolic substrates such as pyruvate and lactate, but MCT8 so far appears to be specific for iodothyronines (14).
References
Heuer H, Maier MK, Iden S, Mittag J, Friesema ECH, Visser TJ, Bauer K 2005 The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology 146:1701–1706
Bernal J, Pekonen F 1984 Ontogenesis of the nuclear 3,5,3'-triiodothyronine receptor in the human fetal brain. Endocrinology 114:677–679
Kester MH, Martinez de Mena R, Obregon MJ, Marinkovic D, Howatson A, Visser TJ, Hume R, Morreale de Escobar G 2004 Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 89:3117–3128
Calvo R, Obregon MJ, Deona CR, Delrey FE, Deescobar GM 1990 Congenital hypothyroidism as studied in rats: crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain. J Clin Invest 86:889–899
Crantz FR, Silva JE, Larsen PR 1982 An analysis of the sources and quantity of 3,5,3'-triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum. Endocrinology 110:367–375
Escobar-Morreale HF, Obregón MJ, Hernández A, Escobar del Rey F, Morreale de Escobar G 1997 Regulation of iodothyronine deiodinase activity as studied in thyroidectomized rats infused with thyroxine or triiodothyronine. Endocrinology 138:2559–2568
Guada?o-Ferraz A, Obregon MJ, St Germain DL, Bernal J 1997 The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci USA 94:10391–10396
Tu HM, Kim SW, Salvatore D, Bartha T, Legradi G, Larsen PR, Lechan RM 1997 Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone. Endocrinology 138:3359–3368
Tsacopoulos M, Magistretti PJ 1996 Metabolic coupling between glia and neurons. J Neurosci 16:877–885
Hennemann G, Docter R, Friesema ECH, DeJong M, Krenning EP, Visser TJ 2001 Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22:451–476
Abe T, Suzuki T, Unno M, Tokui T, Ito S 2002 Thyroid hormone transporters: recent advances. Trends Endocrinol Metab 13:215–220
Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ 2002 Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol 16:2283–2296[Free Full Text]
Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y 2003 Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine. J Biol Chem 278:43489–43495
Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ 2003 Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278:40128–40135
Bernal J 2002 Action of thyroid hormone in brain. J Endocrinol Invest 25:268–288
Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S 2004 A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 74:168–175
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 2004 Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 364:1435–1437
Bates JM, St Germain DL, Galton VA 1999 Expression profiles of the three iodothyronine deiodinases D1, D2, and D3, in the developing rat. Endocrinology 140:844–851
Brockmann K, Dumitrescu AM, Best TB, Hanefeld F, Refetoff S, X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. J Neurology, in press
DeLong GR 1984 The effect of iodine deficiency on neuromuscular development. IDD Newslett 6:1–9(Juan Bernal)
Address all correspondence and requests for reprints to: Prof. Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain.
The developing brain is an important target of thyroid hormones. A complex regulatory network involving transfer of thyroid hormones through the brain barriers, interactions between neurons and glial cells, and deiodinase expression, works to deliver the appropriate amount of T3 to the nuclear receptors. The data provided by Heuer et al. (1) in this issue indicates that specific thyroid hormone transporters may also be an essential part of this regulatory system.
Thyroid hormones influence brain development from about the end of the first trimester of fetal life. The human fetal brain expresses nuclear T3 receptors at least from the 10th week of gestation, and receptor concentration increases 10-fold during the second trimester in brain and other tissues (2). T4 is present in brain and other tissues, such as liver, kidney, and lung, but T3 is detectable only in brain, at concentrations that result in an occupancy of brain T3 receptors around 25%. The source of T4 reaching the fetal brain up to midgestation is mostly of maternal origin (3). Both T4 and T3 cross the placenta and reach the fetal organs, but only T4 appears to cross the fetal blood-brain barrier. Thus, the administration of T3 by constant infusion to pregnant rat dams increased T3 concentrations in all maternal and fetal tissues except the fetal brain (4). In contrast, the administration of T4 increased T3 content in fetal brain as well as in other tissues. There was also a very important difference between the brain and the rest of the tissues. When increasing amounts of T4 were administered to pregnant dams maintained on methimazole, normal concentrations of T3 in the fetal brain were kept over a much wider range of T4 doses than in other tissues.
In adult rats, both T4 and T3 reach the brain from blood, but it was estimated that as much as 80% of the T3 bound to the nuclear receptors was produced locally by type 2 deiodinase (D2) activity (5). As in fetal brain, when either T4 or T3 was administered to hypothyroid rats, the T3 content of the brain was maintained within control values only by T4, but not by T3, infusion (6). Homeostasis of T3 within the brain is maintained within narrow limits by a complex mechanism involving D2 and D3. Several years ago we reported that D2 was predominantly expressed in glial cells of two types, tanycytes and astrocytes (7) (Fig. 1). Tanycytes, in which expression of D2 was also reported by Tu et al. (8), are specialized ependymal cells lining the third ventricle and extending processes to the adjacent hypothalamus and the median eminence. The T3 generated by these cells from cerebrospinal T4 could play a role in TRH-TSH regulation. On the other hand, expression of D2 in the astrocytes suggested to us the existence of interplay between astrocytes and neurons on T3 homeostasis similar to the metabolic coupling between the two cells concerning the glutamate-glutamine cycle or glucose use (9). Astrocytes would produce T3 for neuronal use. As an additional control of neuronal T3 concentration, D3, which degrades T3 to the inactive metabolite diiodothyronine, is expressed in neurons. In this issue, Heuer et al. (1) confirm expression of D2 in the astrocytes and suggest important roles in T3 homeostasis for recently characterized thyroid hormone transporters (Fig. 1).
FIG. 1. Thyroid hormones are transported through the blood-brain barrier (OATP) or the blood-CSF barrier (OATP and MCT8). In the astrocytes and tanycytes T4 is converted to T3 which then enters the neurons through MCT8. In the neurons both T4 and T3 are degraded by D3. T3 from the tanycytes may reach the portal vessels in the median eminence. Other transporters may be present on the astrocyte or tanycyte membranes. In most cases the transport could be bidirectional, although only one direction is shown.
The entry of thyroid hormones into the cells has for a long time been assumed to be by passive diffusion, because thyroid hormones are lipophilic molecules and as such could easily enter the membrane lipid bilayer. Experiments in vivo hardly gave any hint of a saturable process, as was, for example, the binding of T3 to the nucleus, an observation that facilitated the discovery of nuclear receptors. However, in isolated hepatocytes and other cell types, the demonstration of relatively high-affinity sites for both T4 and T3, and the inhibition of cellular uptake by metabolic inhibitors, amino acids, and other chemicals, gave evidence for the physiological significance of thyroid hormone transporters (10). Several molecular entities have been identified as transporters for thyroid hormone (11). They belong to three main families: the organic anion-transporting polypeptides (OATP), the L-amino acid transporters, and the monocarboxylate anion transporters (MCT).
Among the many members of the OATP family, human OATP-F (12) and rat Oatp14 (13) are preferentially expressed in brain. The Oatp14 protein is localized in the border of brain capillary endothelial cells and in the choroid plexus. OATP-F/Oatp14 transports T4 and rT3 much more efficiently than T3, and might be involved in the transport of T4 through the blood-brain barrier and through the choroid plexus, and also in rT3 clearance. The blood-brain barrier is the route by which thyroid hormone is preferentially distributed throughout the brain, and this transporter could facilitate uptake of T4 by the astrocytes. Transfer of thyroid hormone through the choroid plexus achieves only limited diffusion to the brain parenchyma after passage to the cerebrospinal fluid but would allow uptake of T4 by tanycytes and subsequent T3 generation in these cells.
The MCT family comprises up to 14 members, some of which are involved in the transport of important substrates for the brain such as lactate and pyruvate. MCT8 has been shown to act as a specific transporter for T4 and T3 and displays slightly higher affinity for T3 (14). Heuer et al. (1) have also studied the regional expression of MCT8 mRNA. In addition to high expression levels in the choroid plexus, they found that MCT8 is expressed in neurons of the neocortex, hippocampus, basal ganglia, amygdala, hypothalamus, and the Purkinje cells of the cerebellum, all regions known to be sensitive to thyroid hormones (15). Expression of MCT8 in neurons suggests that neuronal uptake of the T3 produced in astrocytes is facilitated by this transporter.
The physiological significance of MCT8 as a transporter for thyroid hormone is supported by the finding of mutations in humans by Dumitrescu et al. (16) and Friesema et al. (17). The syndrome affects children from an early age and consists of severe developmental delay and neurological damage together with an unusually altered pattern of thyroid hormone levels in blood. The patients presented low total and free T4, high total and free T3, and low rT3. TSH was moderately elevated in two of the patients and normal or slightly elevated in the other five. Inactivating mutations of the MCT8 transporter could result in the altered thyroid hormone levels. In vitro uptake of T4 and T3 by fibroblasts isolated from affected males was strongly reduced, and intracellular D2 was increased 6- to 8-fold (17). It is thus hypothesized that the resulting increase in intracellularly generated T3 accumulates in blood because of its poor reuptake into cells. In addition, deficient uptake of T4 and T3 by neurons could reduce degradation by neuronal D3 to rT3 and diiodothyronine, respectively, with increased T3 and decreased rT3. The brain and skin are predominant sites of D3 expression, but their contribution to T3 degradation and to blood rT3 is difficult to estimate (18).
The neurological syndrome caused by MCT8 mutations consists of developmental delays, rotary nystagmus, severe proximal hypotonia with poor head control, spastic quadriplegia, dystonic movements, and impaired gaze and hearing. More recently, a syndrome of paroxysmal dyskinesia has been recognized by Brockmann et al. (19) in the two patients originally described by Dumitrescu et al. (16). The whole clinical picture is so severe that it is pertinent to ask the question of whether the impaired uptake and action of thyroid hormone on neurons could cause such a syndrome. The neurological disorder of endemic cretinism (neurological cretinism) consists of variable degrees of neuromotor affectation with proximal limb girdle spasticity and rigidity, more often affecting the lower extremities, extrapyramidal disorders of rigidity and bradykinesia, deaf-mutism, strabismus, dysarthria, and mental deficiency (20). Epidemiological and physiopathological considerations indicate that this syndrome is most probably a result of lack of thyroid hormone during fetal development, especially before midgestation. This is the period of neuroblast proliferation and maturation of the basal ganglia and cerebral cortex. In the postmortem examination of the maternal uncle of one of the patients, also probably affected, loss of neurons in the cerebral cortex, basal ganglia, and cerebellum was found (16). As mentioned above, the second trimester is also the period when thyroid hormone receptors increase in concentration in the brain. If MCT8 is needed at this stage of development for T3 entry into neurons, mutations of the transporter could also interfere with T3-dependent developmental processes. Knowledge of the ontogenetic patterns of MCT8 in the human fetal brain would certainly be helpful. On the other hand, there is also the possibility that MCT8 mutations interfere with transport of other substrates for brain metabolism that could be even more important than T3 in determining the severity and outcome of the syndrome. Other members of the family transport metabolic substrates such as pyruvate and lactate, but MCT8 so far appears to be specific for iodothyronines (14).
References
Heuer H, Maier MK, Iden S, Mittag J, Friesema ECH, Visser TJ, Bauer K 2005 The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology 146:1701–1706
Bernal J, Pekonen F 1984 Ontogenesis of the nuclear 3,5,3'-triiodothyronine receptor in the human fetal brain. Endocrinology 114:677–679
Kester MH, Martinez de Mena R, Obregon MJ, Marinkovic D, Howatson A, Visser TJ, Hume R, Morreale de Escobar G 2004 Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 89:3117–3128
Calvo R, Obregon MJ, Deona CR, Delrey FE, Deescobar GM 1990 Congenital hypothyroidism as studied in rats: crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain. J Clin Invest 86:889–899
Crantz FR, Silva JE, Larsen PR 1982 An analysis of the sources and quantity of 3,5,3'-triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum. Endocrinology 110:367–375
Escobar-Morreale HF, Obregón MJ, Hernández A, Escobar del Rey F, Morreale de Escobar G 1997 Regulation of iodothyronine deiodinase activity as studied in thyroidectomized rats infused with thyroxine or triiodothyronine. Endocrinology 138:2559–2568
Guada?o-Ferraz A, Obregon MJ, St Germain DL, Bernal J 1997 The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci USA 94:10391–10396
Tu HM, Kim SW, Salvatore D, Bartha T, Legradi G, Larsen PR, Lechan RM 1997 Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone. Endocrinology 138:3359–3368
Tsacopoulos M, Magistretti PJ 1996 Metabolic coupling between glia and neurons. J Neurosci 16:877–885
Hennemann G, Docter R, Friesema ECH, DeJong M, Krenning EP, Visser TJ 2001 Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22:451–476
Abe T, Suzuki T, Unno M, Tokui T, Ito S 2002 Thyroid hormone transporters: recent advances. Trends Endocrinol Metab 13:215–220
Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ 2002 Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol 16:2283–2296[Free Full Text]
Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y 2003 Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine. J Biol Chem 278:43489–43495
Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ 2003 Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278:40128–40135
Bernal J 2002 Action of thyroid hormone in brain. J Endocrinol Invest 25:268–288
Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S 2004 A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 74:168–175
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 2004 Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 364:1435–1437
Bates JM, St Germain DL, Galton VA 1999 Expression profiles of the three iodothyronine deiodinases D1, D2, and D3, in the developing rat. Endocrinology 140:844–851
Brockmann K, Dumitrescu AM, Best TB, Hanefeld F, Refetoff S, X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. J Neurology, in press
DeLong GR 1984 The effect of iodine deficiency on neuromuscular development. IDD Newslett 6:1–9(Juan Bernal)