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Endocrine Abstracts (2014) 34 OC4.3 | DOI: 10.1530/endoabs.34.OC4.3

1Imperial College London, London, UK; 2Queen Mary University of London, London, UK; 3Brno University of Technology, Brno, Czech Republic; 4University of Sheffield, Sheffield, UK; 5Garvan Institute of Medical Research, Sydney, New South Wales, Australia; 6National Cancer Institute, Bethesda, Maryland, USA.


A new genetic disorder has recently been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio, constipation and a variable intellectual deficit, but exhibit a consistently severe skeletal dysplasia. Similar to these patients, Thra1PV/+ mice harbour a mutation that disrupts the C-terminal α-helix of TRα1 and express a dominant negative receptor. Thus, Thra1PV/+ mice represent an excellent disease model for this new disorder. We hypothesized Thra1PV/+ mice could be used to predict the skeletal consequences of human THRA mutations and investigate the effects of T4-treatment. We determined the adult skeletal phenotype in Thra1PV/+ mice and investigated the response to treatment with a supra-physiological dose of thyroxine (1.2 μg/ml in drinking water from 4 until 20 weeks of age).

Adult Thra1PV/+ mice had persistently delayed ossification and short stature but normal bone strength despite high bone mass, suggesting that patients with THRA mutations are unlikely to have an increased risk of fracture. By contrast, gross morphological abnormalities of the bones and joints predict a likely predisposition to osteoarthritis. Although T4-treatment completely suppressed TSH secretion, it had no effect on skeletal maturation, linear growth or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone in the skeleton of Thra1PV/+ mice. Nevertheless, prolonged T4-treatment resulted in abnormally increased bone stiffness and strength due to progressive enlargement of cortical bone, suggesting the potential for detrimental long-term consequences. Furthermore, despite identical T4-treatment, Thra1PV/+ mice exhibited a blunted rise in circulating thyroid hormones, suggesting increased thyroid hormone metabolism in Thra1PV/+ mice.

Our studies establish that TRα1 has an essential role in the developing and adult skeleton, and predict that, in patients with THRA mutations, the severity of skeletal dysplasia and responsiveness to T4-treatment will correlate with the activity of the mutant TRα1.

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