title: A resistance to thyroid hormone syndrome mutant operates through the target gene repertoire of the wild-type thyroid hormone receptor.
abstract: Thyroid hormone receptors (TRs) play crucial roles in vertebrates. Wild-type (WT) TRs function primarily as hormone-regulated transcription factors. A human endocrine disease, Resistance to Thyroid Hormone (RTH)-Syndrome, is caused by inheritance of mutant TRs impaired in the proper regulation of target gene expression. To better understand the molecular basis of RTH we compared the target genes regulated by an RTH-TRβ1 mutant (R429Q) to those regulated by WT-TRβ1. With only a few potential exceptions, the vast majority of genes we were able to identify as regulated by the WT-TRβ1, positively or negatively, were also regulated by the RTH-TRβ1 mutant. We conclude that the actions of R429Q-TRβ1 in RTH-Syndrome most likely reflect the reduced hormone affinity observed for this mutant rather than an alteration in target gene repertoire. Our results highlight the importance of target gene specificity in defining the disease phenotype and improve our understanding of how clinical treatments impact RTH-Syndrome.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, USA.
authors.forename: Robyn
authors.initials: R
authors.lastname: Jimenez
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, USA. Electronic address: mlprivalsky@ucdavis.edu.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Privalsky
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D063990:Gene Ontology; D005822:Genetic Vectors / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D050505:Mutant Proteins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine
keywords: Endocrine disease; RNA-seq; RTH; Target genes; Thyroid hormone receptor