Generalized resistance to thyroid hormone: identification of a novel c-erbA beta thyroid hormone receptor variant (Leu450) in a Japanese family and analysis of its secondary structure by the Chou and Fasman method.

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.