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

• Published in: Baillière's best practice & research. Clinical endocrinology & metabolism Vol. 21; no. 2; pp. 277 - 305
• Main Authors: Refetoff, Samuel, MD, Dumitrescu, Alexandra M., MD, PhD
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.06.2007
• Subjects: Animals; deiodinases; Diagnosis, Differential; Endocrinology & Metabolism; Humans; Iodide Peroxidase - genetics; MCT8; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Membrane Transport Proteins - physiology; metabolism; Models, Biological; Mutation; Pedigree; receptor; Receptors, Thyroid Hormone - genetics; resistance; SECISBP2/SBP2; selenoproteins; thyroid hormone; Thyroid Hormone Resistance Syndrome - epidemiology; Thyroid Hormone Resistance Syndrome - genetics; Thyroid Hormone Resistance Syndrome - pathology; Thyroid Hormone Resistance Syndrome - therapy; Thyroid Hormones - deficiency; Thyroid Hormones - metabolism; Thyroid Hormones - physiology; Thyroid Hormones - secretion; transmembrane transport; transmembrane transport; receptor; thyroid hormone; deiodinases; metabolism; selenoproteins; MCT8; resistance; SECISBP2/SBP2
• ISSN: 1521-690X; 1878-1594
• DOI: 10.1016/j.beem.2007.03.005

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.