RESUMO
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 delta 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.
Assuntos
Hipertireoidismo/genética , Mutação Puntual , Receptores dos Hormônios Tireóideos/genética , Deleção de Sequência , Adulto , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Cromossomos Humanos Par 17 , Análise Mutacional de DNA , Erros de Diagnóstico , Genes , Bócio/genética , Doença de Graves/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Hipertireoidismo/congênito , Deficiência Intelectual/genética , Masculino , Biossíntese de Proteínas , Receptores dos Hormônios Tireóideos/deficiência , TireoidectomiaRESUMO
The yeast HO gene, which encodes an endonuclease involved in initiating mating type interconversion, is expressed in mother cells but not in daughters. It has been demonstrated that the SWI5 gene, which is an activator of HO expression, plays a critical role in this differential mother/daughter expression of HO. In this paper we describe the cloning and sequencing of the SWI5 gene. The predicted amino acid sequence derived from the cloned SWI5 gene shows homology with the repeated DNA-binding domains ('zinc fingers') of Xenopus transcription factor TFIIIA. A region of the HO promoter involved in the SWI5-dependent transcriptional activation of HO was identified by deletion analysis of the HO promoter in the chromosome, and by testing the ability of HO DNA fragments to activate transcription in the context of a heterologous promoter. The SWI5 gene product was overproduced in yeast from the GAL1-10 promoter, since the SWI5 protein is made at very low levels in wild-type strains, and protein extracts were used to demonstrate that the SWI5 protein binds in vitro to a segment of the HO promoter required for transcriptional activation in vivo.