Thyroid hormone receptor α mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice

Abstract

A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4ratio 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 T4treatment, but responses have been inconsistent so far. Thra1PV/+mice express a similar potent dominant-negative mutant TRα1 to affected individuals, and thus represent an excellent disease model.Wehypothesized that Thra1PV/+mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4ameliorates the skeletal abnormalities. Adult female Thra1PV/+mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4treatment suppressed TSH secretion, it had no effect onskeletal maturation, linear growth, orbonemineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4treatment abnormally increased bone stiffnessandstrength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRα1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4treatment, which depend on the severity of the causative mutation. Copyright