GENERALIZED RESISTANCE TO THYROID-HORMONE - IDENTIFICATION OF A NOVELC-ERBA-BETA THYROID-HORMONE RECEPTOR VARIANT (LEU(450)) IN A JAPANESEFAMILY AND ANALYSIS OF ITS SECONDARY STRUCTURE BY THE CHOU AND FASMANMETHOD

Generalized resistance to thyroid hormone (GRTH) is characterized by e levated circulating levels of thyroid hormone in the presence of a eum etabolic state and failure to respond to triiodothyronine. Various poi nt mutations in the c-erbA beta thyroid hormone receptor gene are know n to be responsible for different phenotypes of GRTH. We herein report a new c-erbA beta variant in a Japanese family. The variant consistin g of a cytosine to adenine base substitution at nucleotide position 16 50 altered phenylalanine to leucine in codon 450 in the T-3-binding do main of c-erbA beta. This base substitution was found in one allele of the 2 affected members of the family. The in vitro translation produc ts of this mutant c-erbA beta gene demonstrated a significantly reduce d T-3-binding affinity. The secondary structure of this mutant thyroid hormone receptor predicted by the Chou and Fasman method included a n ew turn in the alpha helix structure in the T-3-binding domain. We als o discuss the secondary structures of the previously reported mutant r eceptors.