Author(s): Dumitrescu AM, Refetoff S
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Abstract BACKGROUND: Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. SCOPE OF REVIEW: The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. MAJOR CONCLUSIONS: Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH. GENERAL SIGNIFICANCE: Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling. Copyright © 2012 Elsevier B.V. All rights reserved.
This article was published in Biochim Biophys Acta
and referenced in Journal of Pharmacogenomics & Pharmacoproteomics