Thyroid hormone receptors and resistance to thyroid hormone disorders

Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor alpha (THRA) and thyroid hormone receptor beta (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone beta (RTH beta), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THR beta to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THR beta alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THR alpha have since been described. These patients have RTH alpha and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-thyroid axis in these individuals is minimally affected, which suggests that the central T-3 feedback loop is not impaired in patients with RTH alpha, in stark contrast to patients with RTH beta.