to obtain direct genetic evidence for the involvement of TR-β signaling through the PI3 kinase in brain development and metabolism, two of the primary physiological effects of thyroid hormone action. Isoforms There are two main classes of the thyroid hormone receptor, alpha and beta. The localization of these subtypes, summarized in Table 1, is largely dependent upon post-transcriptional splicing. Genes on chromosomes 3 and 17 are transcribed and translated into c-erbA gene products. Splicing of these gene products leads to the production of different isoforms. There are three TR-α receptor splice variants encoded by the THRA (thyroid hormone receptor alpha) gene and three TR-β isoform splice variants encoded by the THRB (thyroid hormone receptor beta) gene. Of these variants, thyroxine is only able to bind to four of them: TR-α1, TR-β1, TR-β2, and TR-β3. Disease linkage Certain mutations in the thyroid hormone receptor are associated with thyroid hormone resistance. The clinical diagnosis of thyroid hormone resistance syndrome (THRS) depends on the location of the resistance, which can be localized to the pituitary gland, peripheral tissues, or both. Patients who present with resistance in both tissue types are diagnosed with global resistance to thyroid hormone. Mutations to both TR genes have been observed clinically, however, THRB gene mutations are much more common. THRB gene mutation TR-βresistance an autosomal dominant disease. This means only one copy of the mutated gene on chromosome 3 needs to be inherited in order for an individual to present with this condition. THRB mutation directly affects the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. In a healthy individual, the TR-β2 expressed in the pituitary gland plays a major role in regulating thyroid-stimulating hormone (TSH) levels through negative feedback. TSH stimulates the thyroid to secrete thyroid hormone. Once secreted, thyroid hormone acts on these receptors and inhibits transcription of Tshb. This feedback inhibition stops further TSH production, inhibiting thyroid hormone secretion downstream. When the THRB gene is mutated, the receptors on the pituitary can no longer bind thyroid hormone. Due to this, TSH production and secretion is not regulated to the same degree and the thyroid continues to be stimulated. The elimination of the negative feedback loop results in the heightened levels of thyroid hormone presented by patients with this condition. THRA gene mutation The THRA gene is located on chromosome 17. Not as much information is known about mutations to this gene because it is far less common