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 thyroid hormone action which has been linked to the beta thyroid hormone receptor (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 clinical thyroid resistance. In this report, we describe a patient with GRTH caused by a single C --> A base mutation (nucleotide 1623) in one allele of TR beta (exon 10). The mutation produces a premature translation termination signal (UGA) at codon 446 and predicts expression of a mutant 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, this case represents the first description of a mutation producing premature translation termination of TR beta in association with the syndrome GRTH, and emphasizes the critical role of the carboxyl terminal region of TR beta in mediating both positive and negative regulation of thyroid-responsive target genes in many tissues.