Clinical and molecular aspects of nuclear thyroid hormone action

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

Yeni bir TSH reseptör aktive edici mutasyon ile ilişkili ailevi hipertiroidi: Beş vaka takdimi

Familial non-autoimmune hyperthyroidism, a rare disorder that results from activating germline mutations in the TSH receptor gene, is inherited in an autosomal dominant fashion and has a variable age at onset. Here, we present a family, five members of which were determined to have non-autoimmune hyperthyroidism. Levels of free T3 and free T4 were high and TSH suppressed in two siblings aged 12 and 16, who were admitted due to failure to gain weight and swollen necks. Thyroid autoantibodies were negative and thyroid ultrasonography demonstrated no nodules. A similar situation was detected in their father and two other siblings, none of whom had remarkable complaints. A novel heterozygous missense mutation (c.1906T>A) in the 10th exon of the TSH receptor gene was found in the affected cases. Treatment with methimazole and propranolol was initiated in all cases. During follow-up, one case underwent total thyroidectomy, and radioactive iodine treatment was administered to another. Gain-of-function germline mutations in the TSH receptor should be considered in cases of hyperthyroidism not associated with autoimmune thyroid disease, and family screening, including asymptomatic individuals, should be done

Product lifecycle and choice of transportation modes: Japan’s evidence of import and export

Here we test the hypothesis that commodities at their peak valuation are transported by air and those at their birth and maturity are shipped by sea, and that shippers would choose air for transporting high-valued commodities. We empirically investigated how the product lifecycle of commodities is reflected by shippers' choices of air transportation rather than seaborne transportation. We also assumed that the commodities that achieved substantial innovation in their lifecycles would be moved by air transportation so that these commodities could reach the targeted markets as quickly as possible to avoid the opportunity costs that might be generated by missed business chances. We constructed two unbalanced panel data of 18 commodities (the case of import) and 14 commodities (the case of export) for 24 years from Japan’s custom, demographic, and international statistics. By estimating structural equation systems that consisted of commodity-specific import/export and import/export air ratio functions, we found that the product lifecycle of cargo outgoing from Japan exactly matched the upward and downward move of the air ratio, whereas since incoming commodities are raw materials that have little to do with product lifecycle or matured phase in their lifecycle stage, the peak of commodities’ valuations and the use of air transportation were not necessarily synchronized

A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

Peer reviewe

Hypothyroidism compromises hypothalamic leptin signaling in mice

The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism.status: publishe

Psychomotor Retardation Caused by a Defective Thyroid Hormone Transporter: Report of Two Families with Different MCT8 Mutations

Background/Aims: Monocarboxylate transporter 8 (MCT8) is essential for thyroid hormone (TH) transport in the brain. Mutations in MCT8 are associated with the Allan-Herndon-Dudley syndrome (AHDS), characterized by severe psychomotor retardation and altered serum thyroid parameters. Here we report two novel mutations in MCT8 and discuss the clinical findings. Case Report and Results: We describe 4 males with AHDS from two unrelated families varying in age from 1.5 to 11 years. All 4 patients presented with typical clinical signs of AHDS, including severe psychomotor retardation, axial hypotonia, lack of speech, diminished muscle mass, increased muscle tone, hyperreflexia, myopathic facies, high T3, low T4 and rT3, and normal/mildly elevated TSH levels. Comparison of patients at different ages suggests the progressive nature of AHDS. Genetic analyses identified a novel missense MCT8 mutation (p.G495A) in family 1 and a 2.8-kb deletion comprising exons 3 and 4 in family 2. Functional analysis of p.G495A revealed impaired TH transport varying from 20 to 85% depending on the cell context. Conclusion: Here we report 4 AHDS patients in unrelated Turkish families harboring novel MCT8 mutations. Despite the widely different mutations, the clinical phenotypes are very similar and findings support the progressive nature of AHDS. (C) 2014 S. Karger AG, Base