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Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination

https://doi.org/10.1016/j.beem.2007.03.005Get rights and content

At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor β gene and has been given the acronym RTH. Occurring in ∼1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.

Section snippets

Backgound and physiology

Thyroid hormone (TH), which plays a major role in growth and development, acts on the peripheral tissues of the adult to regulate their level of metabolism. Its action is most dramatic in metamorphosing amphibians, in which it produces resorption of the tadpole tail and budding of limbs to generate the adult frog. In mammals, including man, severe TH deprivation during intrauterine life, and in the immediate postnatal period, results in irreversible damage to the CNS.

Resistance to thyroid

Thyroid hormone action

The expression of TH effects requires the intracellular presence of a sufficient amount of the active hormone, T3. Rapid, nongenomic action is exerted at the level of the plasma membrane and cytoplasm. This involves ion channels, oxidative phosphorylation, and second messengers.11 However, the principal and best-studied effect requires the translocation of the hormone into the nucleus, where it interacts with TRs to regulate (activate or repress) the transcription of target genes. These genes

Cell membrane transporters of thyroid hormone

The tight correlation between serum free TH concentrations and the level of TH-dependent processes, suggesting an equilibrium between the intracellular and serum free fraction of TH, has perpetuated the hypothesis of passive hormonal diffusion into cells.72 However, the identification and characterization of several classes of molecule with different kinetics and substrate preferences has changed this paradigm.73 These proteins belong to different families of solute carriers, organic anions,

Intracellular metabolism of thyroid hormone

The requirement for TH varies with tissue, cell type and time. Control of TH entry into the cell through membrane transporters is apparently insufficient to provide the proper hormone supply. Further fine-tuning is achieved by the generation of active TH or by its inactivation at the site of action. D1 and D2 are 5′-iodothyronine deiodinases that catalyze TH activation by converting T4 to T3. D3, a 5-deiodinase, is the main TH inactivator through conversion of T4 to rT3 and T3 to T2.

Deiodinases

Differential diagnosis

The combination of nonsuppressed (normal or slightly elevated) serum TSH with increased concentrations of T4, T3, or both, is characteristic of the three syndromes of reduced sensitivity to TH (Table 2). Exclusion of serum TH transport protein abnormalities by direct assessment or measurement of the free TH levels (preferably by equilibrium dialysis) is recommended before proceeding with further testing. The laboratory test abnormalities must be confirmed by repeated testing, several weeks or

Acknowledgements

Supported by grants DK17050 and RR00055 from the National Institutes of Health (S.R.) and Howard Hughes Medical Institute Predoctoral Fellowship (A.M.D.).

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