Generalized resistance to thyroid hormone (GRTH) is characterized by elevated circulating levels of thyroid hormone in the presence of a eumetabolic state and failure to respond to triiodothyronine. Various point mutations in the c-erbA beta thyroid hormone receptor gene are known to be responsible for different phenotypes of GRTH. We herein report a new c-erbA beta variant in a Japanese family. The variant consisting of a cytosine to adenine base substitution at nucleotide position 1650 altered phenylalanine to leucine in codon 450 in the T3-binding domain of c-erbA beta. This base substitution was found in one allele of the 2 affected members of the family. The in vitro translation products of this mutant c-erbA beta gene demonstrated a significantly reduced T3-binding affinity. The secondary structure of this mutant thyroid hormone receptor predicted by the Chou and Fasman method included a new turn in the alpha helix structure in the T3-binding domain. We also discuss the secondary structures of the previously reported mutant receptors.