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Mechanisms of Disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 512–523 (2006)Cite this article

Abstract

The actions and the metabolism of thyroid hormone are intracellular events that require the transport of iodothyronines across the plasma membrane. It is increasingly clear that this process does not occur by simple diffusion, but is facilitated by transport proteins. Only recently have iodothyronine transporters been identified at the molecular level, of which organic anion transporting polypeptide 1C1 and monocarboxylate transporter 8 (MCT8) deserve special mention, because of their high activity and specificity for iodothyronines. Organic anion transporting polypeptide 1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the transport of the prohormone T4 across the blood–brain barrier. MCT8 is also expressed in the brain—in particular, in neurons—but also in other tissues. MCT8 seems to be especially important for the uptake of active hormone T3 into neurons, which is essential for optimal brain development. T3 is produced from T4 by type 2 deiodinase in neighboring astrocytes. Neurons express type 3 deiodinase, the enzyme that terminates T3 activity. The SLC16A2 (formerly MCT8) gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe, X-linked, psychomotor retardation and high serum T3 levels. In over 20 families, where affected males have developed this syndrome, several mutations in MCT8 have been identified. The disease mechanism is thought to involve a defect in the neuronal entry of T3 and, therefore, in the action and metabolism of T3 in these cells. This defect results in impaired neurological development and a decrease in T3 clearance.

Key Points

  • Thyroid hormones are extremely important for brain development; neurons are their major target cells

  • Monocarboxylate transporter 8 is essential for uptake of T3 in central neurons and, therefore, for allowing T3 access to its intracellular receptor and to its degrading enzyme D3 in these cells

  • Inactivation of monocarboxylate transporter 8 interferes with the action and metabolism of T3 in neurons and results in impaired neurological development and increased T3 levels

  • Mutation of a thyroid hormone transporter represents a novel mechanism for the pathogenesis of thyroid hormone resistance, which has dramatic consequences

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Figure 1: Transport and deiodination of thyroid hormones
Figure 2: The structure of the SLC16A2 gene, and the location of mutations in it and its product
Figure 3: MCT8, OATP1C1, D2 and D3 expression in peripheral mouse tissues and brain
Figure 4: Levels of thyroid parameters in patients with mutations in SLC16A2, and levels of thyroid hormones and deiodinases in Slc16a2-knockout mice

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Acknowledgements

Our thanks go to all families and collaborators who contributed their efforts towards this work. These studies were supported by grants to ECH Friesema from the Netherlands Organization of Scientific Research, to J Jansen from the Sophia Children's Hospital Foundation for Medical Research, and to H Heuer from the American Thyroid Association.

Author information

Authors and Affiliations

  1. a Post-Doctoral Fellow Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Edith CH Friesema

  2. a PhD Fellow Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Marija Trajkovic

  3. a Professor of Endocrinology at the Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Theo J Visser

  4. a Group Leader the Leibniz Institute for Age Research—Fritz Lipmann Institute, Jena, Germany

    Heike Heuer

  5. a PhD Fellow at the Leibniz Institute for Age Research—Fritz Lipmann Institute, Jena, Germany

    Jurgen Jansen

  6. Professor of Endocrinology at the Max Planck Institute for Experimental Endocrinology, Hannover, Germany

    Karl Bauer

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  1. Edith CH Friesema
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Correspondence to Theo J Visser.

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Friesema, E., Jansen, J., Heuer, H. et al. Mechanisms of Disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nat Rev Endocrinol 2, 512–523 (2006). https://doi.org/10.1038/ncpendmet0262

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