A tight linkage between generalized resistance to thyroid hormone (GRTH) and the thyroid hormone receptor-beta (TR beta) gene is indicated. We evaluated a family with GRTH for the TR beta gene. We found that a new point mutation, consisting of a cytosine to adenine replacement at nucleotide position 1642, resulted in substitution in codon 448 in the T3-binding domain of TR beta. This base substitution was found in only one allele of affected members, but not in unaffected members of the family. The in vitro translation products of this mutant TR beta gene demonstrated significantly reduced T3-binding affinity. Previously, others have reported a kindred with GRTH, in that the same codon was subjected to proline to histidine replacement due to a mutation consisting of a cytosine to adenine replacement at nucleotide position 1643. There appeared to be a significant phenotypic difference between our kindred and that described by others.