Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue 
responsiveness to thyroid hormone. To date, all individuals expressing the RTH 
phenotype have been found to harbor mutations in the thyroid hormone receptor 
beta (TR beta) gene that impair T3-mediated function. We describe a unique 
family in which the dominantly inherited 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-fold the normal replacement doses of L-T4 and L-T3. No other endocrine 
abnormalities were detected. The defect developed de novo in the proposita and 
was transmitted to her two children of unrelated fathers. As cultured 
fibroblasts from the proposita responded poorly to T3 despite a normal 
concentration of TR, other abnormalities in the mediation of T3 action were 
sought. Nucleotide sequences of the TSH beta promoter, containing thyroid 
hormone response elements, and TR-interacting protein 1 were normal. Nuclear 
extracts (NE) of cultured skin fibroblasts from affected individuals of this 
family were tested for their interaction with normal TR beta and thyroid hormone 
response elements by the electrophoretic mobility shift assay. NE from the 
proposita showed a strong additional band compared to NEs from normal 
individuals and patients with RTH caused by TR beta mutations or deletion. Far 
Western analysis of NE from the affected daughter hybridized with labeled TR 
beta demonstrated an additional band that was not seen in NEs from a normal 
control or patients with TR beta gene defects. It is concluded that 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 the RTH phenotype in this family.