A novel mutation of thyroid hormone receptor beta (I431V) impairs corepressor release, and induces thyroid hormone resistance syndrome.
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.
Ferreira Azevedo
Monalisa
M
University of Brasília, DF, Brazil.
Barra
Gustavo Barcelos
GB
Medeiros
Ligiane Dantas de
LD
Simeoni
Luiz Alberto
LA
Naves
Luciana Ansaneli
LA
Neves
Francisco de A Rocha
Fde A
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
D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D037042:Thyroid Hormone Receptors beta