Endocrine Abstracts

The main product of the thyroid is thyroxine (T4). However, the physiological ligand of nuclear thyroid hormone receptors is triiodothyronine, T3. Deiodination of T4 to yield T3 is achieved by 5′-deiodinase activity. Type I-deiodinase (Dio1) was the first deiodinase cloned and its strong expression in liver and kidny, together with the size of these organs, suggested a role for Dio1 in peripheral conversion of T4 to T3. Later, Dio2 and Dio3 were cloned, enzymes with a mo...

Introduction: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific transmembrane transport protein. Inactivating mutations in MCT8 lead to severe mental retardation, the Allan-Herndon-Dudley syndrome. The severity of the Allan-Herndon-Dudley syndrome differs among MCT8 patients. Partial activity of MCT8 can be caused either by mutations affecting the transport mechanism (e.g. substrate interaction, conformational change) or by inefficient protein expression, memb...

With the identification of mutations in the monocarboxylate transporter 8 (MCT8) gene in patients afflicted with the Allan–Herndon–Dudley syndrome (AHDS), the concept of transporter-mediated transmembrane transport of thyroid hormones was finally accepted. Impaired thyroid hormone transport into neurons and pituitary cells is believed to cause severe psychomotor retardation and altered thyroid hormone function tests. MCT8 is a specific thyroid hormone transporter abl...

Deiodinases (Dio1-3) are selenium-dependent enzymes that catalyze the reductive removal of iodine from iodothyronines. Depending on the substrate and the position of the iodine removed, deiodination can generate T3 from T4 or inactivate T3 and T4. Local expression of Dio can help to adjust the intracellular levels of T3 to the physiological needs of the organ without changing circulating T3 concentrations. It has been suggested that hepatic Dio1 generates circulating T3. Howev...

The main product of the thyroid gland, T4, is a prohormone. 5’-deiodination is needed to convert T4 into the active, nuclear receptor-binding hormone, T3. Pharmacological modulation of activating 5’-and inactivating 5-deiodination of iodothyronines would be desirable in a number of medical conditions, including hypothyroidism, hyperthyroidism and various cancers. A structural and mechanistic understanding of deiodinase (DIO) catalysis...

Thyroid hormone transport into cells critically depends on plasma membrane transport proteins. One of these, monocarboxylate transporter 8 (MCT8), is mutated in patients suffering from a form of X-linked mental retardation, the Allan-Herndon-Dudley syndrome. These patients are characterized by abnormal thyroid hormone and TSH plasma levels indicating a role for MCT8 in the regulation of the thyroid hormone axis. Mice lacking the Mct8 gene replicate the thyroid hormone a...

Objective: Mutations in the gene encoding the thyroid hormone transport protein, monocarboxylate transporter 8 (MCT8), underlie severe mental retardation. In vitro expression of mutant transporters was performed to understand phenotypical differences.Methods: We established cell lines stably expressing 16 MCT8 variants in JEG1 and MDCK cells. Several of these mutants have never been analysed before. The cell lines were characterized according to M...

A novel solid-phase-extraction (SPE) method followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) was established for the simultaneous detection and quantification of thyroid hormone profiles in one sample of human or mouse serum.Recovery during preanalytical steps was monitored by addition of an internal deuterated standard (d5-T4) to 200 μl serum, which was deproteinized by adding a precipitating agent consisting of 1% f...

Background: Selenoproteins are involved in oxidative stress defence, cell signalling and hormone metabolism. Accordingly, impairment of selenium (Se) metabolism or transport results in a complex phenotype as exemplified in selenoprotein P knockout mice (SePP-KO). This mouse model is characterized by a disrupted metabolism of Se resulting in neurological and growth defects. Hypothesis: Se impairs regular tissue development by modifying growth signal biosynthesis, anabolic respo...

Thyroid hormones are essential for the proper development of a variety of tissues, especially the nervous system. Their transport into target cells is mediated by specific thyroid hormone transporters like the monocarboxylate transporter 8 (MCT8). Mutations in this X-chromosomal gene in humans lead to a severe phenotype characterized by psychomotor retardation, hypotonia, and a striking derangement of serum thyroid hormone levels: high T3 in the presence of low T4, and no sign...