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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2570
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 2378-2381
Copyright © 2007 by The Endocrine Society

BRIEF REPORT

Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine

Jurgen Jansen1, Edith C. H. Friesema1, Monique H. A. Kester, Carmelina Milici, Maarten Reeser, Annette Grüters, Timothy G. Barrett, Edna E. Mancilla, Johan Svensson, Jean-Louis Wemeau, Maria Heloisa Busi da Silva Canalli, Johan Lundgren, Meriel E. McEntagart, Neil Hopper, Willem Frans Arts and Theo J. Visser

Departments of Internal Medicine (J.J., E.C.H.F., M.H.A.K., C.M., T.J.V.), and Child Neurology (W.F.A.), Erasmus Medical Center, 3015 GE DR Rotterdam, The Netherlands; Department of Pediatrics (M.R.), Juliana Children’s Hospital, 2566 MJ The Hague, The Netherlands; Department of Pediatric Endocrinology (A.G.), Charité Children’s Hospital, Humboldt University Berlin, 10099 Berlin, Germany; Department of Endocrinology (T.G.B.), Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom; Institute of Biomedical Sciences (E.E.M.), Program of Pathophysiology, University of Chile, 6511224 Santiago, Chile; Department of Pediatrics (J.S.), Malmö University Hospital, S-205 02 Malmö, Sweden; Clinique Endocrinologique Marc Linquette (J.-L.W.), Centre Hospitalier Regional Universitaire de Lille, 59037 Lille, France; Medical Clinic Division (M.H.B.d.S.C.), Endocrinology Service, University Hospital, Federal University of Santa Catarina, 88040–970 Florianópolis, Brazil; Department of Child Neurology (J.L.), Children’s Hospital, University Hospital Lund, S-221 85 Lund, Sweden; and Departments of Clinical Genetics (M.E.M.), and Paediatric Endocrinology (N.H.), St. George’s Hospital, London SW17 0QT, United Kingdom

Address all correspondence and requests for reprints to: Theo J. Visser, Department of Internal Medicine, Erasmus Medical Center, Room Ee502, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: t.j.visser{at}erasmus.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: T3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T3 levels.

Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T3.

Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T3 uptake, 2) T3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry.

Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8.

Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T3 in central neurons.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THYROID HORMONE IS essential for the development of the brain (1, 2). The bioavailability of T3 in the brain is locally regulated through the interplay of two types of cells, astrocytes and neurons. Astrocytes express the type II deiodinase that converts the prohormone T4 to T3, which is subsequently transported to the neurons, the major target cells for thyroid hormone in the brain (3, 4). In addition to nuclear T3 receptors, neurons express the type III deiodinase (D3), which catalyzes termination of T3 activity. Multiple transporters are involved in cellular iodothyronine uptake and efflux in different tissues (5, 6). Recent evidence suggests that monocarboxylate transporter 8 (MCT8) is important for T3 uptake into central neurons (7, 8).

The MCT8 gene is located on chromosome Xq13.2; depending on which of the two possible translation start sites is used, it codes for a protein of 613 or 539 amino acids, containing 12 putative transmembrane domains (TMDs). MCT8 is expressed in numerous human tissues, including brain, heart, placenta, lung, kidney, skeletal muscle, and liver. We and others have reported on patients with mutations in the MCT8 gene (9, 10, 11, 12, 13). These patients, all male, show a distinct phenotype of severe psychomotor retardation in combination with elevated serum levels of T3.

In the present study, we provide functional characteristics of six MCT8 mutations. The functional consequences of mutations in MCT8 on cellular uptake and metabolism of T3 were determined in JEG3 cells transfected with wild-type or mutant MCT8 alone or in cells cotransfected with MCT8 and D3.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Serum and DNA analyses

Approval for these studies was obtained from the medical ethical committee of the Erasmus Medical Center. Informed consent was obtained from the parents of all patients. Serum T4, free T4, T3, and TSH were measured by Vitros ECI technology (Immunodiagnostic System; Ortho-Clinical Diagnostics, Beerse, Belgium). The coding sequence of MCT8 was analyzed in patient DNA using intronic primers flanking the six exons.

Cloning and site-directed mutagenesis of human MCT8

Construction of a human MCT8 cDNA-containing pcDNA3 expression vector was described previously (14). The point mutations identified in patients (Table 1Go) were introduced in MCT8 cDNA using the QuickChange Site-Directed Mutagenesis protocol (Stratagene, Amsterdam, The Netherlands) and confirmed by sequencing.


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  		TABLE 1. Nine patients with mutations in MCT8

 
Transfection of JEG3 cells

JEG3 cells were grown at 37 C in DMEM-F12 medium containing 9% fetal bovine serum and 100 nM sodium selenite and transfected at 70–80% confluency using 0.3 µl FuGENE 6 transfection reagent (Roche Diagnostics, Almere, The Netherlands) per 100 ng DNA. For T3 uptake studies and immunoblotting (IB), cells were grown in six-well plates and transfected with 500 ng empty pcDNA3 or pcDNA3 containing wild-type or mutated MCT8 cDNA. Renilla luciferase vector (50 ng; pRL-SV40; Promega, Leiden, The Netherlands) was cotransfected to enable correction for transfection efficiency. For intact-cell T3 metabolism assays, cells were cultured in 24-well plates and cotransfected with 100 ng pcDNA3 containing wild-type or mutant MCT8 and 100 ng pCI-Neo containing D3 cDNA (14). For analysis of D3 activity in cell lysates, JEG3 were cotransfected for 48 h with 500 ng wild-type or mutant MCT8 and 500 ng human D3 cDNA in six-well plates. For immunocytochemistry (ICC), cells were cultured on 15-mm coverslips and transfected with 100 ng cDNA.

T3 uptake and metabolism assays, IB, and ICC

Two days after transfection, cells were rinsed with DMEM-F12 medium plus 0.1% BSA. For the T3 uptake assay, the cells were incubated for 5 min at 37 C in 1.5 ml DMEM-F12/0.1% BSA containing 1 or 100 nM (2 x 105 cpm) [125I]T3 (Amersham Biosciences, Roosendaal, The Netherlands). Incubation was stopped by removing the medium and washing once with DMEM-F12/0.1% BSA. Cells were lysed with 0.1 M NaOH, and the lysates were counted in a {gamma} counter. Renilla luciferase activity was measured in parallel wells according to the protocol of the manufacturer.

For the intact-cell T3 metabolism assay, MCT8 and D3 (co)transfected cells were incubated for 4 h at 37 C in 0.5 ml DMEM-F12/0.1% BSA containing 1 nM (1 x 106 cpm) [125I]T3. After incubation, medium was harvested and analyzed by HPLC as described previously (14). For analysis of D3 activity in cell lysates, cells were harvested in PE buffer [0.1 M phosphate (pH 7.2), 2 mM EDTA] containing 1 mM dithiothreitol and sonicated. Appropriate dilutions of the sonicates were incubated for 1 h at 37 C with 1 nM (2 x 105 cpm) [125I]T3 in 0.1 ml PE buffer containing 10 mM dithiothreitol. Incubations were stopped, and samples were analyzed by HPLC. IB of transfected cell homogenates was performed as described previously (14). For ICC, cells were fixed and permeabilized with 4% paraformaldehyde and 0.2% Triton X-100 and stained with MCT8-specific polyclonal antibody 1306. The plasma membrane was stained using zona occludens 1 antibody (Invitrogen, Breda, The Netherlands). Alexa fluor 488 and 633 (Invitrogen) were used as detection antibodies; analyses were performed on a Zeiss Axiovert 100 confocal microscope (Zeiss, Sliedrecht, The Netherlands) using Zeiss LSM software.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
We report here on nine boys with severe psychomotor retardation, five of which have been presented previously (Table 1Go). The clinical phenotypes and serum thyroid parameters of the additional four patients are similar to those of patients with MCT8 mutations described by us and others. All of our patients have been identified with severe psychomotor retardation, characterized by axial hypotonia, spastic or flaccid quadriplegia, dystonic movements, and absence of speech. Mean serum T4 and free T4 are decreased, TSH is mildly increased, and serum T3 is markedly elevated. Patients are between 2.5 and 18 yr old and come from various ethnic backgrounds.

All nine patients were found to have different hemizygous mutations in MCT8 (Table 1Go). Patient 1 has a 24,527 bp deletion, stretching from 15 kb upstream to 9 kb downstream of exon 1. Patient 2 has a 671C->T missense mutation in exon 2, resulting in an Ala224Val substitution located in the second putative TMD (9, 15). Patient 3 has a 1412T->C mutation in exon 5, resulting in a Leu471Pro substitution located in the ninth TMD (9). Patient 4 has a 2374 bp deletion, which comprises a large part of exon 3, entire intron 3 and exon 4, and part of intron 4. Patient 5 has a nonsense 733C->T mutation in exon 2, resulting in premature translation termination (Arg245stop) (9). Patient 6 has a missense 812G->A mutation in exon 3, resulting in an Arg271His substitution located in the second extracellular loop. Patient 7 has a 14-bp deletion (nucleotides 631–644), resulting in a frame shift and truncation of the protein at amino acid residue 235. Patient 8 has a G->C mutation in the acceptor splice site of exon 3, i.e. ACCT instead of AGCT. RT-PCR analysis of mRNA isolated from fibroblasts of his affected brother indicated the loss of 282 nucleotides from exon 3 and, thus, of 94 amino acids, including TMDs 4–6. Patient 9 has a 3-bp (TCT) deletion in exon 2, leading to deletion of Phe230.

Figure 1AGo shows the uptake of T3 by JEG3 cells transfected with wild-type or mutant MCT8 cDNA after 5 min of incubation at 37 C. Significant T3 uptake was observed in empty pcDNA3-transfected cells. JEG3 cells do not show endogenous expression of MCT8 (14). Therefore, this background uptake is likely facilitated by other, as yet unidentified, transporter(s). Transfection with wild-type MCT8 increased T3 uptake 2.8-fold. Transfection of cells with MCT8 mutants Ala224Val, Leu471Pro, Arg245stop, splice site mutant ex3 –1G->C, and delPhe230 did not increase T3 uptake over control cells. However, transfection with the MCT8 Arg271His mutant induced a modest but significant 1.4-fold increase in T3 uptake (P < 0.05). Uptake experiments using 100 nM T3 produced similar results (data not shown).


Figure 1
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  		FIG. 1. A, T3 uptake in wild-type or mutant MCT8-transfected JEG3 cells, shown as percentage of added T3 after 5 min incubation. Transfection of wild-type MCT8 induces uptake approximately 2.8-fold compared with empty vector-transfected controls. Most mutants do not induce uptake, but Arg271His mutant induces a significant 1.4-fold increase. B, Metabolism of T3 in intact JEG3 cells cotransfected with wild-type or mutant MCT8 and D3. Metabolism is shown as percentage of metabolites (3,3'-diiodothyronine and 3'-monoiodothyronine) in the medium after 4 h incubation. Wild-type MCT8 induces metabolism approximately 6-fold and Arg271His approximately 2-fold. The other mutants do not show induction of metabolism. C, Western blot of homogenates of JEG3 cells transfected with wild-type or mutant MCT8. Specific bands of approximately 60 and 240 kDa, representing monomeric MCT8 and a MCT8-containing protein complex, are detected clearly in wild-type and Ala224Val- and Arg271His-transfected cells. Less protein is detected for Leu471Pro and delPhe230; no expression is seen of splice site mutant ex3 –1G->C and Arg245stop. D, D3 activity in cell lysates, expressed as percentage of activity in cells cotransfected with wild-type MCT8 and D3. No significant differences in D3 activity are observed, indicating that reduced metabolism in intact cells transfected with mutant MCT8 is attributable to decreased intracellular availability of T3 and not to differences in D3 activity. Uptake and metabolism data are presented as mean ± SE of four experiments. *, P < 0.05 vs. control. ND, Not determined; WT, wild type.

 
JEG3 cells transfected with control plasmid or MCT8 cDNA alone did not show significant metabolism of T3, indicating very low deiodination capacity of these cells (data not shown). Figure 1BGo shows that transfection with D3 cDNA resulted in 11% metabolism of T3 after 4 h. Cotransfection of cells with wild-type MCT8 and D3 greatly increased T3 metabolism to approximately 60%. Cotransfection of cells with the MCT8 Ala224Val, Leu471Pro, Arg245stop, or delPhe230 mutants and D3 did not increase T3 metabolism compared with D3 transfection alone. However, cotransfection with the MCT8 Arg271His mutant and D3 showed 20% metabolism, again indicating that some T3 transport is preserved in this mutant.

D3 activity in lysates of JEG3 cells cotransfected with the different MCT8 mutants amounted to 85–123% of that in cells cotransfected with wild-type MCT8 (Fig. 1DGo), indicating that the impaired T3 metabolism in intact cells cotransfected with mutant vs. wild-type MCT8 is indeed attributable to inhibited T3 uptake rather than decreased D3 expression. IB (Fig. 1CGo) showed marked expression of wild-type MCT8 and of mutants Ala224Val and Arg271His, little expression of Leu471Pro and delPhe230, and no expression of splice site mutant ex3 –1G->C and Arg245stop. Control cells transfected with pcDNA3 also showed no expression of MCT8. ICC demonstrated marked plasma membrane expression of wild-type MCT8 and mutant Arg271His, whereas Ala224Val was mainly localized in the cytoplasm. Leu471Pro, ex3 –1G->C, and delPhe230 showed very little expression of protein (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We present nine unrelated young males with severe X-linked psychomotor retardation and elevated serum T3 levels with mutations in the MCT8 gene. We show that these mutations result in loss of function, demonstrated as reduced uptake and subsequent metabolism of T3 in vitro. Several mechanisms may be involved in this loss of function, including reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. The mutant Ala224Val protein is clearly detectable by IB. However, ICC shows the protein to be mostly distributed in the cytoplasm, suggesting that this mutation inhibits trafficking to the plasma membrane. Much less Leu471Pro protein is detected by IB and ICC, suggesting that loss of function is correlated with reduced expression of the protein. The premature Arg245stop found in patient 5 results in a severely truncated MCT8 protein that cannot be detected with our polyclonal MCT8 antibody and does not have any functional activity. Mutant ex3 –1G->C is not detected by IB, and only very limited protein is observed in ICC. This suggests that the expression of this splice variant, although clearly detectable at the RNA level, is very limited at the protein level. The lack of T3 transport by mutant delPhe230 can also be explained by the low expression of this protein. Mutant Arg271His shows significant residual transport capacity. IB shows high expression of the protein, and ICC indicates expression at the plasma membrane. Possibly, the partial loss of function is caused by reduced affinity for T3.

Our findings associate the psychomotor retardation observed in MCT8 patients with loss of T3 transport capacity. This illustrates that MCT8 is crucial for normal thyroid hormone-dependent development of the central nervous system in humans. Thyroid hormone plays a crucial role in processes such as cell migration, dendritic outgrowth, the formation of synapses, and myelination (16). Neurons are the major target cells for thyroid hormone, expressing T3 receptors (17) and D3 and MCT8 (8). Loss-of-function mutations in MCT8 lead to reduced or absent supply of T3 to neurons, resulting in impaired neurological development as well as a reduced clearance of T3 by neuronal D3. The role of MCT8 in neuronal T3 uptake was recently studied in MCT8 knockout mice by Dumitrescu et al. (18) and Trajkovic et al. (19). They show reduced T3 concentrations, increased type II deiodinase activity, and reduced D3 activity in brain, reflecting local hypothyroidism, despite elevated serum T3. Trajkovic et al. (19) also show reduced expression of the thyroid hormone-regulated genes TRH and RC3 in neurons, supporting hypothyroid state at the cellular level. It must be noted, however, that, although MCT8-deficient mice show reduced T3 concentrations in the brain, they do not show an apparent neurological phenotype. This suggests differences in the role of MCT8 in the development of the central nervous system between the two species.

In conclusion, the experiments presented here support the hypothesis of reduced supply of T3 to neurons in patients with mutations in MCT8. The severe psychomotor retardation observed in these patients clearly illustrates the important role of thyroid hormone in human neuronal development.


   Acknowledgments
 
We thank Ronald van der Wal for performing the sequence analyses.


   Footnotes
 
J.J. is supported by Sophia Foundation for Medical Research Project 438. E.C.H.F. and M.H.A.K. are supported by The Netherlands Organization for Scientific Research Grants 916.36.139 and 916.56.186.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 13, 2007

1 J.J. and E.C.H.F. contributed equally to this study. Back

Abbreviations: D3, Type III deiodinase; ex, exon; IB, immunoblotting; ICC, immunocytochemistry; MCT8, monocarboxylate transporter 8; TMD, transmembrane domain.

Received November 22, 2006.

Accepted March 7, 2007.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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