Key Points
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Many proteins can mediate thyroid hormone transport, but only mutations in genes encoding MCT8, MCT10 and OATP1C1 have pathophysiological effects attributed to this process
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MCT8 mutations lead to Allan–Herndon–Dudley syndrome, which is characterized by truncal hypotonia and results in spastic quadriplegia, lack of speech, severe intellectual deficit and altered thyroid hormone concentrations
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MCT8 deficiency impairs the transfer of thyroid hormones across the blood–brain barrier
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Mct8-deficient mice lack neurological impairment possibly due to the presence of Oatp1c1, a T4 transporter, but levels of OATP1C1 in the primate blood–brain barrier are very low
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Histopathological studies of patients with mutations in MCT8 support the concept that defective thyroid hormone action in the brain during development leads to the neurological syndrome
Abstract
The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives. Mutations in SLC16A2, the gene that encodes MCT8, lead to an X-linked syndrome with severe neurological impairment and altered concentrations of thyroid hormones. Histopathological analysis of brain tissue from patients who have impaired MCT8 function indicates that brain lesions start prenatally, and are most probably the result of cerebral hypothyroidism. A Slc16a2 knockout mouse model has revealed that Mct8 is an important mediator of thyroid hormone transport, especially T3, through the blood–brain barrier. However, unlike humans with an MCT8 deficiency, these mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T4 transporter OATP1C1 in the blood–brain barrier; OATP1C1 is more abundant in rodents than in primates and permits the passage of T4 in the absence of T3 transport, thus preventing full cerebral hypothyroidism. In this Review, we discuss the relevance of thyroid hormone transporters in health and disease, with a particular focus on the pathophysiology of MCT8 mutations.
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Change history
07 July 2015
In Table 1 of the originally published article, the Km values for LAT1 and Lat2 were incorrectly labelled and referenced. The Km values for LAT1 shown are for human and not mouse as originally stated. Lat2 was originally labelled as human. These errors have been corrected in the HTML and PDF versions of the article and reference 117 in the original article has been removed.
20 October 2015
In the original published article, reference 93 lists the incorrect article. The correct reference is Arjona, F. J. et al. Identification and functional characterization of zebrafish solute carrier Slc16a2 (Mct8) as a thyroid hormone membrane transporter. Endocrinology 152, 5065–5073 (2011). This error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
The authors would like to acknowledge funding support from the Spanish Ministry of Economy (Plan Nacional de I+D+I, SAF2011-25608), the Centre for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain, and under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, and the Ramon Areces Foundation (CIVP16A1805). We also thank J. Perez for help with the initial artwork.
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Bernal, J., Guadaño-Ferraz, A. & Morte, B. Thyroid hormone transporters—functions and clinical implications. Nat Rev Endocrinol 11, 406–417 (2015). https://doi.org/10.1038/nrendo.2015.66
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