DOMINANT INHERITANCE OF RESISTANCE TO THYROID-HORMONE NOT LINKED TO DEFECTS IN THE THYROID-HORMONE RECEPTOR-ALPHA OR BETA-GENES MAY BE DUE TO A DEFECTIVE COFACTOR

Resistance to thyroid hormone (RTH) is an inherited syndrome of reduce d tissue responsiveness to thyroid hormone. To date, all individuals e xpressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor beta (TR beta) gene that impair T-3-mediated function. We describe a unique family in which the dominantly inherit ed RTH is not associated with abnormalities in the TR beta or TR alpha genes, as determined by gene sequencing and linkage analysis. However , affected family members manifest a severe form of RTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8- to 10-fol d the normal replacement doses of L-T-4 and L-T-3. No other endocrine abnormalities were detected. The defect developed de novo in the propo sita and was transmitted to her two children of unrelated fathers. As cultured fibroblasts from the proposita responded poorly to T-3 despit e a normal concentration of TR, other abnormalities in the mediation o f T-3 action were sought. Nucleotide sequences of the TSH beta promote r, containing thyroid hormone response elements, and TR-interacting pr otein 1 were normal. Nuclear extracts (NE) of cultured skin fibroblast s from affected individuals of this family were tested for their inter action with normal TR beta and thyroid hormone response elements by th e electrophoretic mobility shift assay. NE from the proposita showed a strong additional band compared to NEs from normal individuals and pa tients with RTH caused by TR beta mutations or deletion. Far Western a nalysis of NE from the affected daughter hybridized with labeled TR be ta demonstrated an additional hand that was not seen in NEs from a nor mal control or patients with TR beta gene defects. It is concluded tha t the etiology of RTH is not confined to abnormalities in the TR beta gene. An abnormal cofactor with a specific function in the regulation of thyroid hormone action is probably involved in the expression of th e RTH phenotype in this family.