Thyroid hormone (TH) is important for normal development, differentiation and metabolism. Untreated congenital hypothyroidism leads to cretinism with brain damage, dwarfism, constipation, lethargy and feeding difficulties. TH is synthesized by the thyroid gland, which mainly produces the prohormone T4 and to a lesser extent the biological active T3. Multiple TH transporters have been recognized, an example of a highly specific transporter is monocarboxylate transporter 8 (MCT8). Three deiodinating enzymes (D1-3) have been identified which catalyze the activation of T4 to T3 or the inactivation of T4 to rT3 and of T3 to 3,3’-T2. TH action is mediated by binding of T3 to its nuclear receptors TRα and TRβ. TH action at the cellular level can be regulated at different levels. TH action can be disturbed by defects in TRα or TRβ. Furthermore, it can be regulated at the pre-receptor level by alterations in the intracellular metabolism of TH mediated by the deiodinases, or it can be regulated via alterations in the uptake of TH into the cell. This thesis focused on the clinical and molecular aspects of nuclear thyroid hormone action. We identified one of the first patients with a mutation in TRα1 and subsequently studied their phenotype and possible underlying mechanisms. The phenotype of the RTHα patients identified so far is highly similar but does not completely overlap with the various TRα1 mice models. This is probably dependent on the location and the severity of the mutation. Presumably, further research will reveal new mutations, the role of binding with coactivators or corepressors and improvement of therapy options.

Additional Metadata
Keywords Thyroid hormone, Thyroid hormone production, Thyroid hormone transport, Thyroid hormone metabolism, Thyroid hormone action, Thyroid hormone receptor alpha1
Promotor T.J. Visser (Theo) , R.P. Peeters (Robin)
Publisher Erasmus University Rotterdam
ISBN 978-94-6375-101-8
Persistent URL
Note For copyright reasons there is a partial embargo for this dissertation
van Mol-van Mullem, A.A.A. (2018, November 13). Clinical and molecular aspects of nuclear thyroid hormone action. Erasmus University Rotterdam. Retrieved from