Generalized thyroid hormone resistance due to a deletion of the carboxy terminus of the c-erbA β receptor

Abstract

Generalized resistance to thyroid hormone (GRTH) is a disorder of thyroid hormone action which has been linked to the β thyroid hormone receptor (TRβ) gene. A diverse array of TRβ 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 TRβ (exon 10). The mutation produces a premature translation termination signal (UGA) at codon 446 and predicts expression of a mutant TRβ3 which is truncated by 16 carboxylerminal amino acids (TRβ ▴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 TRβ in association with the syndrome GRTH, and emphasizes the critical role of the carboxyl terminal region of TRβ in mediating both positive and negative regulation of thyroid-responsive target genes in many tissues.