GENERALIZED THYROID-HORMONE RESISTANCE DUE TO A DELETION OF THE CARBOXY-TERMINUS OF THE C-ERBA-BETA RECEPTOR

Generalized resistance to thyroid hormone (GRTH) is a disorder of thyr oid hormone action which has been linked to the beta thyroid hormone r eceptor (TR beta) gene. A diverse array of TR beta mutations have been characterized, and these distinct genotypes have been associated with characteristic patterns of severity and tissue distribution of clinic al thyroid resistance. In this report, we describe a patient with GRTH caused by a single C --> A base mutation (nucleotide 1623) in one all ele of TR beta (exon 10). The mutation produces a premature translatio n termination signal (UGA) at codon 446 and predicts expression of a m utant TR beta which is truncated by 16 carboxyl-terminal amino acids ( TR beta(triangle 446-461)). This sequence was absent in both parents, indicative of a de novo mutation in the proband. To our knowledge, thi s case represents the first description of a mutation producing premat ure translation termination of TR beta in association with the syndrom e GRTH, and emphasizes the critical role of the carboxyl terminal regi on of TR beta in mediating both positive and negative regulation of th yroid-responsive target genes in many tissues.