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Cellular Uptake of Thyroid Hormones

, Ph.D.

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Last Update: June 15, 2016.


The biological activity of thyroid hormone (TH) is regulated at the target tissue level by two important processes, i.e. deiodination and plasma membrane transport. The first process involves the expression of the deiodinase D2, which converts the prohormone T4 to bioactive T3, and/or of the deiodinase D3 which converts both T4 and T3 to inactive metabolites. Intracellular metabolism and action of TH in target cells as well as transcellular TH transport across, for instance, the blood-brain barrier (BBB) and the intestinal wall depends on the expression of transporters facilitating uptake and/or efflux of iodothyronines.

Recently, several important TH transporters have been identified, including monocarboxylate transporter 8 (MCT8), MCT10 and organic anion transporting polypeptide 1C1 (OATP1C1). The physiological relevance of MCT8 has been demonstrated in studies of male patients with the Allan-Herndon-Dudley syndrome, characterized by severe psychomotor retardation and abnormal TH levels caused by hemizygous mutations of the X-linked MCT8 gene. In human brain, MCT8 appears to be important in particular for T4 and T3 transport across the BBB and for T3 uptake in neurons, whereas OATP1C1 is predominantly involved in T4 uptake in astrocytes to allow its conversion to T3 by D2 also expressed in these cells. MCT10 also transports aromatic amino acids and its physiological role in tissue TH transport remains to be established. For complete coverage of this and related areas of Endocrinology, visit our free web-book, .


It was thought for a long time that thyroid hormone (TH) crosses the plasma membrane of tissue cells by simple diffusion since iodothyronines are lipophilic compounds which would easily pass the lipid bilayer of the plasma membrane. However, it has become increasingly clear that diffusion plays a minor role, if any, in TH transport across the plasma membrane. Rather, TH is transported into cells by specific carrier-mediated mechanisms. In the second half of the 20th century, many studies have been published about the biochemical characterization of TH transport mechanisms in a variety of cell types. In general, these studies have indicated that cellular TH transport is a saturable process which in liver cells may be Na+ dependent and in other cell types may be inhibited by aromatic and/or aliphatic amino acids. Early studies of cellular TH transport have been extensively reviewed in 2001 (1) and only some of them will be mentioned here.

About 80% of circulating T3 is produced outside the thyroid gland by peripheral conversion of T4, and only 20% is directly secreted by the thyroid gland (2). T3 is considered to be the major bioactive TH, whereas T4 is mainly a prohormone that becomes activated upon its conversion to T3 (2). Most TH actions are initiated by binding of T3 to its nuclear receptors in target cells (3,4). Therefore, the biological activity of TH is determined largely by the intracellular T3 concentration, which depends on a) the circulating concentration of T3 and its precursor T4; b) the activities of deiodinases that catalyze the production (D1, D2) or degradation (D1,D3) of T3; and c) the activities of transporters which mediate the cellular uptake or efflux of T3 and T4 (Fig. 1). It should be noted that TH bioactivity may be regulated in an autocrine fashion as shown in Fig. 1, or in a paracrine fashion, where T3 production and action take place in the same cell or in separate cells, respectively.

Fig. 1.Thyroid hormone transport, metabolism and action in a target cell.

Fig. 1Thyroid hormone transport, metabolism and action in a target cell.

Recently, three relatively specific TH transporters have been identified. OATP1C1 is a member of the organic anion transporting polypeptide family, which shows preference for T4 above T3, and is expressed almost exclusively in brain (5). In human brain, OATP1C1 is importantly expressed in astrocytes, where it facilitates entry of T4 allowing its conversion to T3 also expressed in these cells (6). MCT8 and MCT10 are members of the monocarboxylate transporter family. While MCT10 is also known to transport aromatic amino acids, no other substrates have been identified for MCT8 than iodothyronines and iodotyrosines (7-9). MCT8 and MCT10 are expressed in various tissues (10). In human brain, MCT8 is importantly expressed in endothelial cells of the blood-brain barrier (BBB) as well as in neurons (6). Mutations in the MCT8 transporter have been identified in male patients with the Allan-Herndon-Dudley syndrome, characterized by severe X-linked psychomotor retardation and elevated serum T3 levels (11-14).


Organic anion transporting polypeptides (OATPs) represent a large family of homologous proteins, many of which have been shown to transport different iodothyronines and their sulfate conjugates (Table 1) (15-17). The genes coding for these transporters are now referred as the SLCO family. The OATPs accept a wide range of substrates, not only anionic but also neutral and sometimes even cationic compounds. Some members are expressed in a single tissue, whereas others have a wider tissue distribution. The SLCO1A2, 1B1, 1B3 and 1C1 genes are clustered together with a related pseudogene on human chromosome 12p12 (17). The encoded OATPs have all been shown to transport iodothyronines (18). Of these, OATP1B1 and 1B3 are expressed specifically in the liver, OATP1C1 is expressed only in brain and testis, and OATP1A2 is expressed in brain, liver and kidney. In terms of TH transport, OATP1C1 is the most intriguing as it shows a high specificity and affinity towards T4 and rT3. In mouse brain, Oatp1c1 is localized both in capillary, the choroid plexus, and astrocytes, but in human brain localization of OATP1C1 in endothelial cells is negligible (5,19-22). Therefore, the primary role of OATP1C1 in human brain appears to be the transport of T4 into astrocytes to allow its conversion to T3 by D2 that is also expressed in astrocytes.

Table 1Characteristics of human thyroid hormone transporters

GeneProteinChrTissue distributionRef.
SLCO1A2OATP1A212p12Brain, kidney, liver(18,111,112)
SLCO1C1OATP1C112p12Brain, cochlea, testis(5,115)
SLCO3A1OATP3A115q26Brain, testis(116)
SLCO4C1OATP4C15q21.2Kidney, other(117)
SLC7A5LAT116q24.3Multiple, tumors(41)
SLC7A8LAT214q11.2Multiple, tumors(41)
SLC16A2MCT8Xq13.2Brain, liver, kidney, heart, thyroid etc(8,9)

It should be realized that the organization of the OATP1 subfamily is very different in humans than in mice and rats (Fig. 2) (23). Although human, mouse and rat OATP1C1 are clearly orthologues, the OATP1A branch has only 1 member in humans (1A2) but 4 members in mice (1A1,4-6) and 5 members in rats (1A1,3-6), whereas the OATP1B branch has 2 members in humans (1B1,3) and one member in rats and mice (1B2). Therefore, mice and rats are not good animal models for TH transport by members of the OATP1A/B subfamily. Considering the different cellular distribution of OATP1C1 in human and mouse brain, the same precaution may also apply to this transporter.

OATPs transport their substrates in a Na-independent manner. The solute carrier family 22 (SLC22) also contains many organic anion transporters (OATs) and organic cation transporters (OCTs) (24), but information about the possible transport of TH by any of these transporters has not been published. We have demonstrated that the Na-taurocholate co-transporting polypeptide (NTCP, SLC10A1) facilitates uptake of the different iodothyronines as well as their sulfates (25,26). The SLC10 family contains 7 members of which NTCP is expressed exclusively in liver (27-29). SLC10A2 is another bile acid transporter expressed in the intestine and kidney. SLC10A6 transports different organic anions but substrates for the other SLC10 transporters have not yet been identified. NTCP is the only SLC10 family member capable of transporting TH (26).

Interestingly, NTCP has recently been identified as the receptor involved in the infection of liver cells by hepatitis B virus (HBV) and hepatitis D virus (HDV) (30). This NTCP-mediated internalization of HBV and HBD is specifically inhibited by the novel drug Myrcludex B, a synthetic peptide derived from the HBV/HBD surface protein preS1 (30). Myrcludex B also inhibits bile acid transport by NTCP (31,32) and it would be interesting to know if it affects TH transport into the liver. Clinical trials are now conducted with this drug in hepatitis B and D patients (33).

Amino Acid Transporters

Iodothyronines are a particular class of amino acids built from two tyrosine residues. Therefore, it is no surprise that amino acid transporters, in particular the L and T-type amino acid transporters, are involved in TH uptake into several tissues (34-38). L-type transporters mediate uptake of large neutral, branched-chain and aromatic amino acids, whereas T-type transporters are specific for the aromatic amino acids Phe, Tyr and Trp.

Four L-type transporters (LAT1-4) have been identified, two of which (LAT1,2) belong to the heterodimeric amino acid transporter family. These transporters consist of a heavy chain and a light chain, linked through a disulfide bond (39). There are 2 possible heavy chains, SLC3A1 (rBAT) and SLC3A2 (4F2hc or CD98), and in humans there are 13 possible light chains belonging to the SLC7 gene family. The 4F2 or CD98 cell surface antigen is expressed in many tissues, especially on activated lymphocytes and tumor cells. 4F2hc is a glycosylated protein with a single transmembrane domain, whereas the light chains are not glycosylated and have 12 transmembrane domains (40). LAT1 and LAT2 consist of the SLC3A2 heavy chain in combination with the SLC7A5 and SLC7A8 light chain, respectively. They are obligate exchangers, implying that the cellular uptake of extracellular substrates is tightly coupled to the efflux of intracellular substrates.

Significant Na-independent transport of iodothyronines has been observed in Xenopus oocytes expressing heterodimeric transporters consisting of human SLC3A2 and either human SLC7A5 (LAT1) or mouse SLC7A8 (LAT2) (Table 1) (41). The rate of iodothyronine uptake by the 4F2hc/LAT1 transporter decreased in the order 3,3’-T2 > T3 ~ rT3 > T4. Apparent Km values were found to be in the micromolar range, being lowest for T3 (1.5 µM) (41).

Ritchie et al. have reported on the stimulation of T3 transport in oocytes injected with mRNA for 4F2hc and for the IU12 Xenopus LAT1 homolog (42). They have also shown that overexpression of the heterodimeric L type transporter in cells results in increased intracellular T3 availability and, thus, augmented T3 action (43). Furthermore, they demonstrated T3 uptake via the 4F2hc/LAT1 transporter into human BeWo placental choriocarcinoma cells, suggesting that this transporter plays a role in the trans-placental transfer of maternal TH to the fetus (44). Indeed both LAT1 and LAT2 have been localized in the human placenta, in particular in cytotrophoblasts (45-48).

TH transport by LAT1 and LAT2 has recently been characterized in more detail, and a structural model of LAT2 has been obtained (49-51). LAT1 facilitates cellular uptake of all iodothyronines tested with a clear preference for 3,3’-T2 and rT3. LAT2 also shows significant cellular uptake of T3 and, in particular, 3,3’-T2. Both LAT1 and LAT2 also markedly facilitate cellular entry of 3-iodotyrosine (MIT) (51).

In addition to LAT1 and LAT2, two other L-type amino acid transporters have recently been identified in the SLC43 family. LAT3 (SLC43A1) and LAT4 (SLC43A2) are monomeric proteins containing 12 trans-membrane domains, which apparently do not require ancillary proteins for proper expression in the plasma membrane (52). Both LAT3 and LAT4 especially facilitate the cellular efflux of their substrates, including 3,3’-T2 and MIT (51). The function of the third member of this small family (SLC43A3) is unknown.

A T-type amino acid transporter (TAT1) has been cloned from rats and humans, showing transport of Phe, Tyr and Trp (53,54). This protein is a member of the monocarboxylate transporter family, and is also called MCT10 (SLC16A10). The MCT family consists of 14 members, and earned its name because MCT1-4 have been characterized as monocarboxylate transporters (55). Endogenous substrates are being recognized for other MCT family members, such as β-hydroxybutyrate for MCT7 (56), carnitine for MCT9 (57), and carnitine for MCT12 (58) The degree of homology between MCT proteins is especially high for MCT1-4 and for MCT8/10. In contrast to the initial failure to demonstrate TH transport by MCT10, we have demonstrated that both MCT8 and MCT10 are highly effective iodothyronine transporters (Table 1) (7-9).

MCT8 and MCT10

MCT8 and MCT10 have identical gene structures; both consist of 6 exons and 5 introns, with a particularly long first intron (~100 kb). The MCT10 gene is located on human chromosome 16q21-q22 and codes for a protein of 515 amino acids. The MCT8 gene is located on human chromosome Xq13.2 and has 2 possible translation start sites, coding for proteins of 613 or 539 amino acids (Fig. 2). The significance of the N-terminal extension of long versus short human MCT8 (indicated in yellow in Fig. 2) remains to be investigated. A patient has been reported with psychomotor retardation associated with a Met to Leu mutation (M1L) at the upstream translation start site. However this mutation was also identified in a healthy relative (59), suggesting that the long MCT8 protein does not have a crucial physiological function. Moreover, a recent study indicated that if the long MCT8 protein is generated it undergoes effective ubiquitination and proteasomal degradation (60). Most species, including mice and rats, only express the short MCT8 protein as they lack the first translation start site. Functional studies of human MCT8 have been carried out so far by expression of the short protein.

Both MCT8 and MCT10 proteins have 12 putative transmembrane domains, with both N- and C-terminal ends located on the inside of the plasma membrane. The common amino acids in MCT8 and MCT10 are indicated in green in Fig. 2, showing a high degree of homology in particular in the transmembrane domains. Unique to the MCT8 structure is the presence of PEST domains in the N-terminal intracellular part of the protein, rich in Pro (P), Glu (E), Ser (S) and Thr (T) residues. The function of these domains is unknown. MCT8 is expressed in many tissues, including human liver, kidney, heart, brain, placenta, adrenal gland, skeletal muscle, and thyroid. MCT10 also shows a wide tissue distribution, with particularly high expression in human skeletal muscle, intestine, kidney and pancreas (10).

Fig. 2.Structure of the human MCT8 protein with 12 transmembrane domains. The blue lines represent the plasma membrane. The N- and C-terminal domains are located in the cytoplasm. The N-terminal extension of long vs. short MCT8 protein generated using the first or the second translation start site is indicated in yellow. The amino acid identity with human MCT10 is indicated in green.

Fig. 2

Structure of the human MCT8 protein with 12 transmembrane domains. The blue lines represent the plasma membrane. The N- and C-terminal domains are located in the cytoplasm. The N-terminal extension of long vs. short MCT8 protein generated using the first or the second translation start site is indicated in yellow. The amino acid identity with human MCT10 is indicated in green.

After the cloning of MCT8 in 1994 (61), no reports on the biological function or the transported substrates have been published until Friesema et al. identified rat MCT8 as a specific TH transporter (8). Expression of rat Mct8 in Xenopus oocytes induced a ~10-fold increase in iodothyronine uptake, much greater than that induced by any other transporter, including rat NTCP, rat OATP1A1 and human LAT1 (8). Although rat MCT8 does not discriminate between T4, T3, rT3 and 3,3’-T2, it does not transport iodothyronine sulfates, the amino acids Phe, Tyr, Trp and Leu, or the monocarboxylates lactate and pyruvate. Apparent Km values amount to 2-5 µM for the different iodothyronines in the absence of protein in the medium. T4 and T3 transport are largely Na+ independent (8).

Subsequent studies in mammalian cells transfected with human MCT8 or MCT10 cDNA have demonstrated that both transporters effectively facilitate transmembrane TH transport (7,9). Co-transfection of the high-affinity cytoplasmic TH-binding protein mu-crystallin (CRYM) strongly augments the cellular accumulation of iodothyronines compared with cells transfected with MCT8 or MCT10 alone. These and other findings suggest that MCT8 and MCT10 facilitate both cellular uptake and efflux of T4 and T3. MCT10 appears to transport T3 better than MCT8 whereas the opposite is true for T4. Transfection of MCT8 or MCT10 into cells that express D1, D2 or D3 results in a marked increase in the intracellular metabolism of different iodothyronine substrates (7,9).


Worldwide, over 100 families have been reported where males are affected by severe psychomotor retardation associated with a particular combination of abnormal serum TH levels. A large family with this X-linked mental retardation (XLMR) syndrome was first reported in 1944 by Allan, Herndon and Dudley (62,63). Since then, this disorder is usually referred to as the Allan-Herndon-Dudley syndrome (AHDS). Only 60 years later it was realized that patients with AHDS also have abnormal TH levels (11,12,64).

Usually, patients with AHDS are born at term following an uncomplicated pregnancy with a normal birthweight, body length and head circumference. During the first 6 months a general hypotonia is noticed. During development the truncal hypotonia remains, whereas the distal hypotonia progresses into dystonia and spasticity. The truncal hypotonia results in poor head control. Growth is relatively normal, but final body length is reduced and body weight is usually extremely low with obvious signs of muscle wasting. There is also progressive microcephaly. In the first 2 years of life, brain MRI shows clearly delayed myelination. Although myelination improves in subsequent years, it never really normalizes. This is supported by a recent study of post-mortem brains from a fetal and a 11-year old AHDS patient (65). Based on observations of delayed myelination, AHDS has also been referred to as a Pelizaeus-Merzbacher-like disorder (PMLD) (66).

Although in some families the clinical phenotype is somewhat milder, AHDS patients are usually incapable of sitting, standing or walking independently, and do not develop any speech. They are severly mentally retarded with IQ values <40. Feeding is a problem in AHDS patients as they have difficulties swallowing; aspiration is a frequent cause of pneumonia. For a detailed description of the clinical features of patients with AHDS, the reader is referred to recent literature (66-69).

AHDS patients have a characteristic combination of abnormal serum TH levels (68). Both T4 and FT4 levels are low-normal to clearly reduced, whereas serum T3 and FT3 are markedly elevated. Serum rT3 is always low. Consequently, the serum T3/T4 and T3/rT3 ratios are strongly elevated. Serum TSH is usually within the normal range, but the mean serum TSH level in AHDS patients is about twice that in healthy controls. Serum SHBG levels are markedly elevated, and several studies have reported on elevated serum lactate levels in young patients (70,71).

In 2004, it was demonstrated by the group of Refetoff and by our group that AHDS represents a TH resistance syndrome caused by a defect in TH uptake in target cells due to mutations in MCT8. Since then, MCT8 mutations have been identified in over 100 families with AHDS. These mutations include 1) deletions affecting one or more exons, 2) frame-shift mutations resulting in scrambled and often truncated proteins, 3) splice site mutations, 4) nonsense mutations resulting in truncated proteins; 5) deletions or insertions of one or more codons and, thus, amino acids, 6) missense mutations asociated with single amino acid substitutions. A list of missense mutations is provided in Table 2.

Table 2Missense MCT8 mutations in AHDS patients

Exon 1Exon 2Exon 3Exon 4Exon 5Exon 6
p.R271H (72,120-124)
p. L433H
p.L471P (11,125,126)
p.A224V (11,72,118,130,131)
p.R445C (79,133)
p.G564R (75,134)
p.S290F (81,135)
p.P321L (66,142)

The larger deletions, frame shift mutations and nonsense mutations are obviously deleterious for MCT8 function. The functional consequences of single amino acid substitutions, deletions or insertions have been investigated in cells transfected with wild-type or mutated MCT8. Most mutations were found to result in an amost complete loss of TH transport by MCT8. However, the extent to which these mutations affect MCT8 function depends on the type of cell used for transfection for reasons which need to be fully explored (72-75). Studies of the localization of wild-type and mutant MCT8 protein have indicated two distinct pathogenic mechanisms, in that certain mutations interfere with the trafficking of the transporter to the plasma membrane, while other mutations allow proper routing of MCT8 but interfere with the substrate translocation process (73,76,77). The functional consequences of MCT8 mutations have also been demonstrated using fibroblasts cultured from skin biopsies, showing that T4 and T3 uptake by cells from AHDS patients is markedly reduced compared with cells cultured from healthy controls (75,78-82).


Studies in humans and animals have indicated that MCT8 is expressed in a variety of tissues, including brain. The distribution of MCT8 expression in mouse brain has been studied in detail by Heuer et al (83). These studies have demonstrated that MCT8 is predominantly expressed in neurons in different brain areas, including hippocampus, cerebral cortex, striatum, hypothalamus and cerebellum. In addition, MCT8 is importantly expressed in capillary endothelial cells, the choroid plexus, and tanycytes which line the third ventricle (83,84). MCT8 expression in neurons coincides with expression of D3. D2 is largely expressed in adjacent astrocytes. In mouse brain, the T4 transporter OATP1C1 is expressed in capillaries, in the choroid plexus and in astrocytes (83-86). However, in primate brain localization of OATP1C1 in capillaries appears to be negligible (22,87).

MCT8 (KO) mice have been studied in the laboratories of Heuer (88-90), Refetoff (91-94), Bernal (95-97) and Schweizer (98-100). In contrast to the severe neurological phenotype in male patients with MCT8 mutations, neither hemizygous MCT8 KO male mice nor homozygous MCT8 KO female mice show an obvious phenotype. However, they show the same abnormal serum thyroid parameters as patients with MCT8 mutations, i.e. a large decrease in T4, a large increase in serum T3, and slightly elevated TSH levels. In addition, MCT8 KO mice show the following features: 1) normal brain T4 uptake but impaired brain T3 uptake, 2) decreased brain T4 and T3 contents, 3) increased D2 and decreased D3 activities in brain, 4) normal liver T4 and T3 uptake, 5) increased kidney T4 and T3 uptake, 6) increased kidney T4 and T3 contents, and 7) increased D1 activity in both liver and kidney (90).

The paradoxical increase in renal T4 and T3 uptake in MCT8 KO mice is unexplained, but the increase in renal T4 content in combination with the increased D1 expression may account for an enhanced renal T4 to T3 conversion, and thus contribute to the decrease in serum T4 and increase in serum T3 (90). In addition, there is evidence suggesting that thyroidal hormone secretion is affected by MCT8 inactivation, perhaps leading to preferential T3 secretion (89,92). Since MCT8 is expressed in the hypothalamus, inactivation of MCT8 is associated with an impaired feedback of TH at the hypothalamic level, contributing to the slightly increased serum TSH level (88,101).

In addition to MCT8 KO mice, a number of other interesting mouse models have been generated which in addition to MCT8 are also deficient in other TH-related genes. Liao et al (102) have studied the effects of the deletion of D1 and/or D2 on serum and brain TH levels in MCT8 KO and WT mice. The results indicate that D1 plays an important role in the altered TH homeostasis in MCT8 KO mice, probably involving and increased T4 to T3 conversion in the thyroid and the kidneys (89,90,92,103). In a recent study, the effect of MCT8 deletion was investigated in D3 deficient mice (104). Inactivation of D3 in mice is associated with marked morbidity and mortality, which is largely prevented by deletion of MCT8. The mechanism by which MCT8 deletion improves the phenotype of D3 deficient mice is unknown.

Of special interest are studies using mice which in addition to MCT8 are also deficient in other TH transporters, such as MCT8/MCT10 (105) and MCT8/LAT2 (106) double knockout (DKO) mice. The additional deficiency of LAT2 or MCT10 results in interesting changes in TH levels compared with MCT8 only KO mice, although deletion of MCT10 or LAT2 alone have little effect on TH homeostasis (105-107). Perhaps most interesting are the findings obtained in MCT8/OATP1C1 DKO mice (21). In contrast to the only mild reduction in brain T3 levels and the lack of an obvious phenotype in mice deficient in MCT8 alone or OATP1C1 alone (108), MCT8/OATP1C1 DKO mice show a dramatic decrease in brain T3 content associated with a markedly impaired neurodevelopment (21). These findings suggest overlapping activities of MCT8 and OATP1C1 in TH transport in the brain, as they are both capable of transporting T4 across the BBB. Apparently, development of the human brain is more vulnerable to mutations in MCT8, since OATP1C1 is not significantly expressed in the human BBB and thus cannot compensate for the loss of MCT8.

Figure 3 shows a schematic of the regulation of T3 supply to neuronal target cells, based largely on studies by Heuer et al (21) and Bernal et al (109). The steps involved in this process include 1) TH transport across the BBB by both OATP1C1 and MCT8 in mice and by MCT8 alone in humans, 2) uptake of T4 in astrocytes by OATP1C1, 3) conversion of T4 to T3 by D2 in astrocytes, 4) release of T3 from the astrocytes by an unidentified transporter, 5) uptake of T3 in neurons by MCT8. These neurons may also express D3 for termination of T3 activity. MCT8 may also be involved in T3 uptake by oligodendrocytes, but this remains to be established. This schema is an oversimplification as, for instance, it ignores the importance of TH transport across the blood-CSF barrier by MCT8 and OATP1C1.

Fig. 3.Schematic of steps involved in the supply of bioactive T3 to target cells in the brain. In contrast to the mouse brain, OATP1C1 does not seem to play an important role in T4 transport across the blood-brain barrier. (Courtesy of Drs. Steffen Mayerl and Heike Heuer).

Fig. 3

Schematic of steps involved in the supply of bioactive T3 to target cells in the brain. In contrast to the mouse brain, OATP1C1 does not seem to play an important role in T4 transport across the blood-brain barrier. (Courtesy of Drs. Steffen Mayerl and Heike Heuer).


TH plays an essential role in brain development. This requires optimal spatio-temporal regulation of T3 supply to brain target cells, in particular neurons. MCT8 is supposed to be crucial for T4 and T3 transport across the BBB and may also play an important role in T3 uptake by neurons. Inactivation of MCT8 results in an impaired development of the central nervous system and thus in severe psychomotor retardation. It is also possibe that MCT8 is more important for T3 uptake in certain subsets of neurons than for others. This may result in a dysbalance of T3 supply to different neuronal populations and thus in a defect in the coordinated development of neuronal networks in the brain.

In addition to the TH dysregulation in the brain, the effects of MCT8 mutations on the thyroid state of peripheral tissues should also be considered. Usually, the heart appears to function normally in MCT8 patients despite exposure to highly elevated serum T3 levels. This suggest a partially impaired cardiac T3 upake in case of a MCT8 mutation, implying the involvement of additional TH transporters in the heart. MCT8 patients show extensive muscle wasting and increased serum SHBG levels, which likely reflect a hyperthyroid state of the skeletal muscles and liver, respectively (hepatic SHBG production is increased by TH). This would indicate that MCT8 inactivation does not impair muscle and liver T3 uptake, suggesting a more important role of other transporters. Finally, findings in MCT8 KO mice suggest that the kidneys are also in a hyperthyroid state in MCT8 patients, but there is no direct evidence for this assumption.


Much progress has been made in recent years with the identification of TH transporters and their role in the tissue-specific regulation of TH bioactivity in health and disease. However, it is likely that important TH transporters still remain to be discovered. For instance, none of the TH transporters characterized recently at the molecular level have the properties of transporters involved in TH uptake in liver cells, such as nanomolar affinities, ATP and Na+ dependence, as determined in previous studies (1). Further, the physiological relevance of OATP1C1 and MCT10 need to be demonstrated. Although it has been demonstrated that mutations in MCT8 cause severe psychomotor retardation, the pathogenic mechanism has not been established. For this it is essential to know exactly where MCT8 is expressed in the human brain and other tissues. A beginning has been made with the treatment of AHDS patients with T3 analogues which do not require MCT8 for cellular uptake, such as DITPA (110) and Triac (, but further work is needed to develop an optimal therapy for these patients.


  1. Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 2001; 22:451-476
  2. 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
  3. Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001; 81:1097-1142
  4. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94:355-382
  5. Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ. Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol 2002; 16:2283-2296
  6. Bernal J. Thyroid hormones in brain development and function. 2015;
  7. 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
  8. 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
  9. Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH. Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 2006; 20:2761-2772
  10. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet 2008; 23:22-44
  11. 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
  12. 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
  13. Dumitrescu AM, Refetoff S. Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action. 2000;
  14. Bernal J. Thyroid Hormones in Brain Development and Function. 2000;
  15. Hagenbuch B. Cellular entry of thyroid hormones by organic anion transporting polypeptides. Best Pract Res Clin Endocrinol Metab 2007; 21:209-221
  16. Suzuki T, Abe T. Thyroid hormone transporters in the brain. Cerebellum 2008; 7:75-83
  17. Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 2004; 447:653-665
  18. van der Deure WM, Peeters RP, Visser TJ. Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters. J Mol Endocrinol 2010; 44:1-11
  19. 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: high affinity transporter for thyroxine. J Biol Chem 2003; 278:43489-43495
  20. Tohyama K, Kusuhara H, Sugiyama Y. Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier. Endocrinology 2004;
  21. Mayerl S, Muller J, Bauer R, Richert S, Kassmann CM, Darras VM, Buder K, Boelen A, Visser TJ, Heuer H. Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest 2014; 124:1987-1999
  22. 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 monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier. Endocrinology 2008; 149:6251-6261
  23. Hagenbuch B, Stieger B. The SLCO (former SLC21) superfamily of transporters. Mol Aspects Med 2013; 34:396-412
  24. Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 2013; 34:413-435
  25. Friesema EC, Docter R, Moerings EP, Stieger B, Hagenbuch B, Meier PJ, Krenning EP, Hennemann G, Visser TJ. Identification of thyroid hormone transporters. Biochem Biophys Res Commun 1999; 254:497-501
  26. Visser WE, Wong WS, van Mullem AA, Friesema EC, Geyer J, Visser TJ. Study of the transport of thyroid hormone by transporters of the SLC10 family. Mol Cell Endocrinol 2010; 315:138-145
  27. Doring B, Lutteke T, Geyer J, Petzinger E. The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr 2012; 70:105-168
  28. Claro da Silva T, Polli JE, Swaan PW. The solute carrier family 10 (SLC10): beyond bile acid transport. Mol Aspects Med 2013; 34:252-269
  29. Anwer MS, Stieger B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch 2014; 466:77-89
  30. Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol 2016; 64:S32-40
  31. Haag M, Hofmann U, Murdter TE, Heinkele G, Leuthold P, Blank A, Haefeli WE, Alexandrov A, Urban S, Schwab M. Quantitative bile acid profiling by liquid chromatography quadrupole time-of-flight mass spectrometry: monitoring hepatitis B therapy by a novel Na(+)-taurocholate cotransporting polypeptide inhibitor. Anal Bioanal Chem 2015; 407:6815-6825
  32. Slijepcevic D, Kaufman C, Wichers CG, Gilglioni EH, Lempp FA, Duijst S, de Waart DR, Elferink RP, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SF. Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice. Hepatology 2015; 62:207-219
  33. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, Lehr T, Lempp FA, Wedemeyer H, Haag M, Schwab M, Haefeli WE, Blank A, Urban S. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B - first results of a Phase Ib/IIa study. J Hepatol 2016;
  34. Lakshmanan M, Goncalves E, Lessly G, Foti D, Robbins J. The transport of thyroxine into mouse neuroblastoma cells, NB41A3: the effect of L-system amino acids. Endocrinology 1990; 126:3245-3250
  35. Blondeau JP, Beslin A, Chantoux F, Francon J. Triiodothyronine is a high-affinity inhibitor of amino acid transport system L1 in cultured astrocytes. J Neurochem 1993; 60:1407-1413
  36. Zhou Y, Samson M, Osty J, Francon J, Blondeau JP. Evidence for a close link between the thyroid hormone transport system and the aromatic amino acid transport system T in erythrocytes. J Biol Chem 1990; 265:17000-17004
  37. Zhou Y, Samson M, Francon J, Blondeau JP. Thyroid hormone concentrative uptake in rat erythrocytes. Involvement of the tryptophan transport system T in countertransport of tri-iodothyronine and aromatic amino acids. Biochem J 1992; 281 ( Pt 1):81-86
  38. Yan Z, Hinkle PM. Saturable, stereospecific transport of 3,5,3'-triiodo-L-thyronine and L-thyroxine into GH4C1 pituitary cells. J Biol Chem 1993; 268:20179-20184
  39. Fotiadis D, Kanai Y, Palacin M. The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med 2013; 34:139-158
  40. Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y. CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 2004; 447:532-542
  41. Friesema EC, Docter R, Moerings EP, Verrey F, Krenning EP, Hennemann G, Visser TJ. Thyroid hormone transport by the heterodimeric human system L amino acid transporter. Endocrinology 2001; 142:4339-4348
  42. Ritchie JW, Peter GJ, Shi YB, Taylor PM. Thyroid hormone transport by 4F2hc-IU12 heterodimers expressed in Xenopus oocytes. J Endocrinol 1999; 163:R5-9
  43. Ritchie JW, Shi YB, Hayashi Y, Baird FE, Muchekehu RW, Christie GR, Taylor PM. A role for thyroid hormone transporters in transcriptional regulation by thyroid hormone receptors. Mol Endocrinol 2003; 17:653-661
  44. Ritchie JW, Taylor PM. Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J 2001; 356:719-725
  45. Loubiere LS, Vasilopoulou E, Bulmer JN, Taylor PM, Stieger B, Verrey F, McCabe CJ, Franklyn JA, Kilby MD, Chan SY. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 2010; 31:295-304
  46. Loubiere LS, Vasilopoulou E, Glazier JD, Taylor PM, Franklyn JA, Kilby MD, Chan SY. Expression and function of thyroid hormone transporters in the microvillous plasma membrane of human term placental syncytiotrophoblast. Endocrinology 2012; 153:6126-6135
  47. Vasilopoulou E, Loubiere LS, Lash GE, Ohizua O, McCabe CJ, Franklyn JA, Kilby MD, Chan SY. Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner. Hum Reprod 2014; 29:1161-1172
  48. Vasilopoulou E, Loubiere LS, Martin-Santos A, McCabe CJ, Franklyn JA, Kilby MD, Chan SY. Differential triiodothyronine responsiveness and transport by human cytotrophoblasts from normal and growth-restricted pregnancies. J Clin Endocrinol Metab 2010; 95:4762-4770
  49. Hinz KM, Meyer K, Kinne A, Schulein R, Kohrle J, Krause G. Structural insights into thyroid hormone transport mechanisms of the L-type amino acid transporter 2. Mol Endocrinol 2015; 29:933-942
  50. Kinne A, Wittner M, Wirth EK, Hinz KM, Schulein R, Kohrle J, Krause G. Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3'-Diiodothyronine across the Plasma Membrane. Eur Thyroid J 2015; 4:42-50
  51. Zevenbergen C, Meima ME, Lima de Souza EC, Peeters RP, Kinne A, Krause G, Visser WE, Visser TJ. Transport of Iodothyronines by Human L-Type Amino Acid Transporters. Endocrinology 2015; 156:4345-4355
  52. Bodoy S, Fotiadis D, Stoeger C, Kanai Y, Palacin M. The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol Aspects Med 2013; 34:638-645
  53. Kim DK, Kanai Y, Chairoungdua A, Matsuo H, Cha SH, Endou H. Expression cloning of a Na+-independent aromatic amino acid transporter with structural similarity to H+/monocarboxylate transporters. J Biol Chem 2001; 276:17221-17228
  54. Kim do K, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, Enomoto A, Cha SH, Goya T, Endou H. The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics 2002; 79:95-103
  55. Halestrap AP. The SLC16 gene family - structure, role and regulation in health and disease. Mol Aspects Med 2013; 34:337-349
  56. Hugo SE, Cruz-Garcia L, Karanth S, Anderson RM, Stainier DY, Schlegel A. A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes Dev 2012; 26:282-293
  57. Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B, Altmaier E, CardioGram, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmuller G, Kottgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, Milburn MV, Prehn C, Raffler J, Ried JS, Romisch-Margl W, Samani NJ, Small KS, Wichmann HE, Zhai G, Illig T, Spector TD, Adamski J, Soranzo N, Gieger C. Human metabolic individuality in biomedical and pharmaceutical research. Nature 2011; 477:54-60
  58. Abplanalp J, Laczko E, Philp NJ, Neidhardt J, Zuercher J, Braun P, Schorderet DF, Munier FL, Verrey F, Berger W, Camargo SM, Kloeckener-Gruissem B. The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter. Hum Mol Genet 2013; 22:3218-3226
  59. Frints SG, Lenzner S, Bauters M, Jensen LR, Van Esch H, des Portes V, Moog U, Macville MV, van Roozendaal K, Schrander-Stumpel CT, Tzschach A, Marynen P, Fryns JP, Hamel B, van Bokhoven H, Chelly J, Beldjord C, Turner G, Gecz J, Moraine C, Raynaud M, Ropers HH, Froyen G, Kuss AW. MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. Eur J Hum Genet 2008; 16:1029-1037
  60. Zwanziger D, Schmidt M, Fischer J, Kleinau G, Braun D, Schweizer U, Moeller LC, Biebermann H, Fuehrer D. The long N-terminus of the human monocarboxylate transporter 8 is a target of ubiquitin-dependent proteasomal degradation which regulates protein expression and oligomerization capacity. Mol Cell Endocrinol 2016;
  61. Lafreniere RG, Carrel L, Willard HF. A novel transmembrane transporter encoded by the XPCT gene in Xq13.2. Hum Mol Genet 1994; 3:1133-1139
  62. Allan W, Herndon CN, Dudley FC. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Mental Defic 1944; 48:325-334
  63. Schwartz CE, Ulmer J, Brown A, Pancoast I, Goodman HO, Stevenson RE. Allan-Herndon syndrome. II. Linkage to DNA markers in Xq21. Am J Hum Genet 1990; 47:454-458
  64. 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
  65. Lopez-Espindola D, Morales-Bastos C, Grijota-Martinez C, Liao XH, Lev D, Sugo E, Verge CF, Refetoff S, Bernal J, Guadano-Ferraz A. Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination. J Clin Endocrinol Metab 2014; 99:E2799-2804
  66. 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
  67. 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
  68. 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
  69. 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
  70. 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
  71. 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
  72. Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Gruters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ. Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. J Clin Endocrinol Metab 2007; 92:2378-2381
  73. 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
  74. Kinne A, Roth S, Biebermann H, Koehrle J, Gruters A, Schweizer U. Surface translocation and T3 uptake of mutant MCT8 proteins are cell type-dependent. Journal of molecular endocrinology 2009; 43:263-271
  75. Visser WE, Jansen J, Friesema EC, Kester MH, Mancilla E, Lundgren J, van der Knaap MS, Lunsing RJ, Brouwer OF, Visser TJ. Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations. Hum Mutat 2009; 30:29-38
  76. Kersseboom S, Kremers GJ, Friesema EC, Visser WE, Klootwijk W, Peeters RP, Visser TJ. Mutations in MCT8 in patients with Allan-Herndon-Dudley-syndrome affecting its cellular distribution. Mol Endocrinol 2013; 27:801-813
  77. Kinne A, Roth S, Biebermann H, Kohrle J, Gruters A, Schweizer U. Surface translocation and tri-iodothyronine uptake of mutant MCT8 proteins are cell type-dependent. J Mol Endocrinol 2009; 43:263-271
  78. Visser WE, Swagemakers SM, Ozgur Z, Schot R, Verheijen FW, van Ijcken WF, van der Spek PJ, Visser TJ. Transcriptional profiling of fibroblasts from patients with mutations in MCT8 and comparative analysis with the human brain transcriptome. Hum Mol Genet 2010; 19:4189-4200
  79. Capri Y, Friesema EC, Kersseboom S, Touraine R, Monnier A, Eymard-Pierre E, Des Portes V, De Michele G, Brady AF, Boespflug-Tanguy O, Visser TJ, Vaurs-Barriere C. Relevance of different cellular models in determining the effects of mutations on SLC16A2/MCT8 thyroid hormone transporter function and genotype-phenotype correlation. Hum Mutat 2013; 34:1018-1025
  80. Visser WE, Vrijmoeth P, Visser FE, Arts WF, van Toor H, Visser TJ. Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation. Clin Endocrinol (Oxf) 2013; 78:310-315
  81. Armour CM, Kersseboom S, Yoon G, Visser TJ. Further insights into the Allan-Herndon-Dudley Syndrome: Clinical and functional characterization of a novel MCT8 mutation. PLOS ONE 2015;
  82. Kersseboom S, Horn S, Visser WE, Chen J, Friesema EC, Vaurs-Barriere C, Peeters RP, Heuer H, Visser TJ. In vitro and mouse studies support therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Mol Endocrinol 2015:me00009999
  83. 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
  84. 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
  85. Schnell C, Shahmoradi A, Wichert SP, Mayerl S, Hagos Y, Heuer H, Rossner MJ, Hulsmann S. The multispecific thyroid hormone transporter OATP1C1 mediates cell-specific sulforhodamine 101-labeling of hippocampal astrocytes. Brain Struct Funct 2015; 220:193-203
  86. Wittmann G, Szabon J, Mohacsik P, Nouriel SS, Gereben B, Fekete C, Lechan RM. Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents. Endocrinology 2015; 156:1552-1564
  87. Ito K, Uchida Y, Ohtsuki S, Aizawa S, Kawakami H, Katsukura Y, Kamiie J, Terasaki T. Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. J Pharm Sci 2011; 100:3939-3950
  88. 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
  89. 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
  90. 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
  91. Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology 2006; 147:4036-4043
  92. 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
  93. Di Cosmo C, Liao XH, Ye H, Ferrara AM, Weiss RE, Refetoff S, Dumitrescu AM. Mct8-deficient mice have increased energy expenditure and reduced fat mass that is abrogated by normalization of serum T3 levels. Endocrinology 2013; 154:4885-4895
  94. Ferrara AM, Liao XH, Gil-Ibanez P, Marcinkowski T, Bernal J, Weiss RE, Dumitrescu AM, Refetoff S. Changes in thyroid status during perinatal development of MCT8-deficient male mice. Endocrinology 2013; 154:2533-2541
  95. 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
  96. 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
  97. Rodrigues TB, Ceballos A, Grijota-Martinez C, Nunez B, Refetoff S, Cerdan S, Morte B, Bernal J. Increased oxidative metabolism and neurotransmitter cycling in the brain of mice lacking the thyroid hormone transporter SLC16A2 (MCT8). PLoS One 2013; 8:e74621
  98. 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
  99. 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
  100. 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
  101. Alkemade A, Friesema EC, Kalsbeek A, Swaab DF, Visser TJ, Fliers E. Expression of thyroid hormone transporters in the human hypothalamus. J Clin Endocrinol Metab 2011; 96:E967-971
  102. 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
  103. Wirth EK, Rijntjes E, Meyer F, Kohrle J, Schweizer U. High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase. Eur Thyroid J 2015; 4:87-91
  104. Patrizia Stohn J, Elena Martinez M, Matoin K, Morte B, Bernal J, Anne Galton V, St Germain D, Hernandez A. MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated with the Absence of a Functional Type 3 Deiodinase. Endocrinology 2016:en20161162
  105. Muller J, Mayerl S, Visser TJ, Darras VM, Boelen A, Frappart L, Mariotta L, Verrey F, Heuer H. Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency. Endocrinology 2014; 155:315-325
  106. Nunez B, Martinez de Mena R, Obregon MJ, Font-Llitjos M, Nunes V, Palacin M, Dumitrescu AM, Morte B, Bernal J. Cerebral cortex hyperthyroidism of newborn mct8-deficient mice transiently suppressed by lat2 inactivation. PLoS One 2014; 9:e96915
  107. Braun D, Wirth EK, Wohlgemuth F, Reix N, Klein MO, Gruters A, Kohrle J, Schweizer U. Aminoaciduria, but normal thyroid hormone levels and signalling, in mice lacking the amino acid and thyroid hormone transporter Slc7a8. Biochem J 2011; 439:249-255
  108. 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
  109. Bernal J, Guadano-Ferraz A, Morte B. Thyroid hormone transporters--functions and clinical implications. Nat Rev Endocrinol 2015; 11:406-417
  110. Verge CF, Konrad D, Cohen M, Di Cosmo C, Dumitrescu AM, Marcinkowski T, Hameed S, Hamilton J, Weiss RE, Refetoff S. Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab 2012; 97:4515-4523
  111. Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, Onogawa T, Suzuki T, Asano N, Tanemoto M, Seki M, Shiiba K, Suzuki M, Kondo Y, Nunoki K, Shimosegawa T, Iinuma K, Ito S, Matsuno S, Abe T. Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology 2001; 142:2005-2012
  112. Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 2001; 120:525-533
  113. Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D, Nomura H, Unno M, Suzuki M, Naitoh T, Matsuno S, Yawo H. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 1999; 274:17159-17163
  114. van der Deure WM, Friesema EC, de Jong FJ, de Rijke YB, de Jong FH, Uitterlinden AG, Breteler MM, Peeters RP, Visser TJ. Organic anion transporter 1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism. Endocrinology 2008; 149:4695-4701
  115. van der Deure WM, Hansen PS, Peeters RP, Kyvik KO, Friesema EC, Hegedus L, Visser TJ. Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation. Endocrinology 2008; 149:5307-5314
  116. Huber RD, Gao B, Sidler Pfandler MA, Zhang-Fu W, Leuthold S, Hagenbuch B, Folkers G, Meier PJ, Stieger B. Characterization of two splice variants of human organic anion transporting polypeptide 3A1 isolated from human brain. Am J Physiol Cell Physiol 2007; 292:C795-806
  117. Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, Abe M, Satoh F, Unno M, Hishinuma T, Inui K, Ito S, Goto J, Abe T. Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A 2004; 101:3569-3574
  118. Kim JH, Kim YM, Yum MS, Choi JH, Lee BH, Kim GH, Yoo HW. Clinical and endocrine features of two Allan-Herndon-Dudley syndrome patients with monocarboxylate transporter 8 mutations. Horm Res Paediatr 2015; 83:288-292
  119. Thevenon J, Duffourd Y, Masurel-Paulet A, Lefebvre M, Feillet F, El Chehadeh-Djebbar S, St-Onge J, Steinmetz A, Huet F, Chouchane M, Darmency-Stamboul V, Callier P, Thauvin-Robinet C, Faivre L, Riviere JB. Diagnostic odyssey in severe neurodevelopmental disorders: Towards clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet 2016;
  120. Raymond F, Whibley A, Price S, Rosser E, Rahman N, Holder S, Stewart F, Tarpey P, Futreal A, Stratton M, Gold I. Raised T3 levels and mutations in MCT8 (SLC16A2) cause X-linked cerebral palsy and mental retardation. Eur J Med Genet 2008; 14:60
  121. Fuchs O, Pfarr N, Pohlenz J, Schmidt H. Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation. Dev Med Child Neurol 2009; 51:240-244
  122. Hu H, Wrogemann K, Kalscheuer V, Tzschach A, Richard H, Haas SA, Menzel C, Bienek M, Froyen G, Raynaud M, Van Bokhoven H, Chelly J, Ropers H, Chen W. Mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing. Hugo J 2009; 3:41-49
  123. Kientz C, Herbepin Granados V, Lebrun M, Touraine R. 2012 DETERMINATION D'UN RATIO DES HORMONES THYROÏDIENNES T3/T4 COMME MARQUEUR PREDICTIF DE MUTATION DU GENE MCT8. 6èmes Assises de Génétique Humaine et Médicale; 2012; Marseille.
  124. Riess A, Kohlhase J, Grasshoff U, Schöning M, Riess OH, Tzschach A. Allan-Herndon-Dudley syndrome: increased serum triiodothyronine (T3) is a key diagnostic marker. Eur J Hum Genet 2013; 21:161
  125. Redin C, Gerard B, Lauer J, Herenger Y, Muller J, Quartier A, Masurel-Paulet A, Willems M, Lesca G, El-Chehadeh S, Le Gras S, Vicaire S, Philipps M, Dumas M, Geoffroy V, Feger C, Haumesser N, Alembik Y, Barth M, Bonneau D, Colin E, Dollfus H, Doray B, Delrue MA, Drouin-Garraud V, Flori E, Fradin M, Francannet C, Goldenberg A, Lumbroso S, Mathieu-Dramard M, Martin-Coignard D, Lacombe D, Morin G, Polge A, Sukno S, Thauvin-Robinet C, Thevenon J, Doco-Fenzy M, Genevieve D, Sarda P, Edery P, Isidor B, Jost B, Olivier-Faivre L, Mandel JL, Piton A. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014; 51:724-736
  126. Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Genni AD, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S. MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol 2013; 28:795-800
  127. Boccone L, Dessi V, Meloni A, Loudianos G. Allan-Herndon-Dudley syndrome (AHDS) in two consecutive generations caused by a missense MCT8 gene mutation. Phenotypic variability with the presence of normal serum T3 levels. Eur J Med Genet 2013; 56:207-210
  128. Dateki S, Haraguchi K, Sato T, Nakatomi A, Fujiwara M, Sakurai M, Namba N, Ozono K, Moriuchi H. A novel MCT8 mutation in a Japanese patient with Allan-Herndon-Dudley syndrome. Horm Res 2013; 80:360
  129. 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
  130. Yamamoto T, Shimojima K, Umemura A, Uematsu M, Nakayama T, Inoue K. SLC16A2 mutations in two Japanese patients with Allan–Herndon–Dudley syndrome. Human Genome Variation 2014; 1
  131. Wood T, Hobson D, Browning B, Rogers C, Skinner C, Ardinger HH, Collins F, Aronsky A, Friez MJ, Schwartz CE. The utilization of T3/T4 screening of males with MR of unknown etiology to identify patients with Allan-Herndon-Dudley syndrome. Eur J Hum Genet 2008; 16:26
  132. Philips AK, Siren A, Avela K, Somer M, Peippo M, Ahvenainen M, Doagu F, Arvio M, Kaariainen H, Van Esch H, Froyen G, Haas SA, Hu H, Kalscheuer VM, Jarvela I. X-exome sequencing in Finnish families with intellectual disability--four novel mutations and two novel syndromic phenotypes. Orphanet J Rare Dis 2014; 9:49
  133. Ramos HE, Morandini M, Carre A, Tron E, Floch C, Mandelbrot L, Neri N, De Sarcus B, Simon A, Bonnefont JP, Amiel J, Desguerre I, Valayannopoulos V, Castanet M, Polak M. Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care. Eur J Endocrinol 2011; 164:309-314
  134. Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, Hahn CD, Kannu P, Kobayashi J, Minassian BA, Moharir M, Siriwardena K, Weiss SK, Weksberg R, Snead OC, 3rd. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 2015; 56:707-716
  135. Ono E, Ariga M, Oshima S, Hayakawa M, Imai M, Ochiai Y, Mochizuki H, Namba N, Ozono K, Miyata I. Three novel mutations of the MCT8 (SLC16A2) gene: individual and temporal variations of endocrinological and radiological features. Clinical Pediatric Endocrinology 2016; 25:23-35
  136. Anik A, Kersseboom S, Demir K, Catli G, Yis U, Bober E, van Mullem A, van Herebeek RE, Hiz S, Abaci A, Visser TJ. Psychomotor retardation caused by a defective thyroid hormone transporter: report of two families with different MCT8 mutations. Horm Res Paediatr 2014; 82:261-271
  137. Ono E, Ariga M, Oshima S, Hayakawa M, Imai M, Ochiai Y, Matsushima S, Miyata I, Namba N, Ozono K, Ida H. Endocrinological investigations in two cases of MCT8 abnormality with novel mutations in the SLC16A2 gene. 95th Annual Meeting of The Endocrine Society2013:SUN-618.
  138. La Piana R, Vanasse M, Brais B, Bernard G. Myelination Delay and Allan-Herndon-Dudley Syndrome Caused by a Novel Mutation in the SLC16A2 Gene. J Child Neurol 2015; 30:1371-1374
  139. Ugrasbul F, H.H. A. A patient presenting with central hypothyroidism, developmental delay and poor head control. Should we be checking T3 levels? Horm Res 2009; 72:458-459
  140. Noguchi A, Takahashi I, Shoji Y, Oyamada M, Takahashi T. Transient acidosis in infancy with a novel variant in MCT8 (Monocarboxylate transporter 8) gene. Hormone Research 2009; 72:310-311
  141. Gika AD, Siddiqui A, Hulse AJ, Edward S, Fallon P, McEntagart ME, Jan W, Josifova D, Lerman-Sagie T, Drummond J, Thompson E, Refetoff S, Bonnemann CG, Jungbluth H. White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. Dev Med Child Neurol 2010; 52:475-482
  142. Papadimitriou A, Dumitrescu AM, Papavasiliou A, Fretzayas A, Nicolaidou P, Refetoff S. A novel monocarboxylate transporter 8 gene mutation as a cause of severe neonatal hypotonia and developmental delay. Pediatrics 2008; 121:e199-202
  143. Langley KG, Trau S, Bean LJ, Narravula A, Schrier Vergano SA. A 7-month-old male with Allan-Herndon-Dudley syndrome and the power of T3. Am J Med Genet A 2015; 167A:1117-1120
  144. Kobayashi S, Onuma A, Inui T, Wakusawa K, Tanaka S, Shimojima K, Yamamoto T, Haginoya K. Clinical course and images of four familial cases of Allan-Herndon-Dudley syndrome with a novel monocarboxylate transporter 8 gene mutation. Pediatr Neurol 2014; 51:414-416
  145. Fu J, Refetoff S, Dumitrescu AM, Weiss RE. OR29-3: Whole-Exome Sequencing Identified a Novel MCT8 Gene Mutation in a Child with Mild Cognitive, Motor and Behavior Abnormalities. 2014;
  146. Faruk Aydin O, Kara C, Jones J, Wood TC, May MM, Friez MJ, Schwartz CE. Allan-Herndon-Dudley syndrome caused by a novel MCT8/SLC16A2 mutation in a Turkish family. Horm Res 2013; 80:352-353
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