title: A novel mutation of thyroid hormone receptor beta (I431V) impairs corepressor release, and induces thyroid hormone resistance syndrome.
abstract: Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRbeta). We describe a large Brazilian family harboring a novel mutation affecting TRbeta gene and inducing RTH. A 14-year-old girl was found to have elevated free T4 and free T3 plasma concentrations in coexistence with unsuppressed TSH and a questionable goiter. The diagnosis of RTH was verified by identification of a novel mutation (I431V) in the TRbeta gene. Sixteen asymptomatic relatives of the proposita are also affected by the mutation. Functional studies showed that I431V mutation exerts dominant-negative effect on wild type TRbeta, mainly by impairment of ligand-dependent release of corepressor SMRT. The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals.
authors.affiliation: University of Brasília, DF, Brazil.
authors.forename: Monalisa
authors.initials: M
authors.lastname: Ferreira Azevedo
authors.forename: Gustavo Barcelos
authors.initials: GB
authors.lastname: Barra
authors.forename: Ligiane Dantas de
authors.initials: LD
authors.lastname: Medeiros
authors.forename: Luiz Alberto
authors.initials: LA
authors.lastname: Simeoni
authors.forename: Luciana Ansaneli
authors.initials: LA
authors.lastname: Naves
authors.forename: Francisco de A Rocha
authors.initials: Fde A
authors.lastname: Neves
mesh_terms: D000293:Adolescent; D001938:Brazil; D018929:Cell Culture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D037042:Thyroid Hormone Receptors beta