Thyroid Hormone Receptor α Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice

A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor alpha 1 (TR alpha 1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T-4 treatment, but responses have been inconsistent so far. Thra1(PV/+) mice express a similar potent dominant-negative mutant TR alpha 1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1(PV/+) mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T-4 ameliorates the skeletal abnormalities. Adult female Thra1(PV/+) mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T-4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T-4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TR alpha 1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T-4 treatment, which depend on the severity of the causative mutation.