A POINT MUTATION IN THE 3,5,3'-TRIIODOTHYRONINE-BINDING DOMAIN OF THYROID-HORMONE RECEPTOR-BETA ASSOCIATED WITH A FAMILY WITH GENERALIZED RESISTANCE TO THYROID-HORMONE

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.