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Endocrine Abstracts (2016) 44 S8.1 | DOI: 10.1530/endoabs.44.S8.1

1Leibniz Research Institute f. environmental Medicine, Düsseldorf, Germany; 2Leibniz Institute on Aging, Jena, Germany.


Thyroid hormone (TH) actions and metabolism are intracellular events that require the transport of TH across the plasma membrane. This process is facilitated by TH transporters of which the monocarboxylate transporter 8 (MCT8), encoded by the Slc16a2 gene, has been most intensively analyzed. In humans, inactivating mutations in the X-linked MCT8 gene are associated with a severe form of psychomotor retardation in combination with abnormal serum TH parameters. The clinical picture (also known as Allan-Herndon-Dudley syndrome) clearly underscores the significance of MCT8 for proper brain development as well as normal TH metabolism and signaling. In mice, however, Mct8 deficiency does not grossly affect brain development whereas the endocrine abnormalities of the patients are fully replicated.

Our studies revealed that in the mouse CNS, another TH transporter is present that can partially compensate for the absence of Mct8. Whereas Mct8 plays a prominent role in facilitating the uptake of the active hormone T3 into the brain, the organic anion transporting peptide Oatp1c1 (Slco1c1) mediates the transport of T4 across the blood-brain barrier. Consequently, mice deficient in both transporters (Mct8/Oatp1c1 dko mice) exhibit a pronounced hypothyroid situation in the CNS whereas peripheral organs are in a thyrotoxic state.

A first phenotypic description of Mct8/Oatp1c1 dko mice revealed distinct deficits in neuronal differentiation as well as pronounced locomotor deficiencies. The latter phenotype may be explained by a reduced myelination, a retarded cerebellar development and cortical as well as striatal abnormalities. Interestingly, application of the TH analog Triac during early postnatal periods was sufficient to normalize brain abnormalities and significantly improved locomotor functions of Mct8/Oatp1c1 dko mice. These data underscore the potential of Triac as a therapeutic option for patients with AHDS.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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