text: Resistance to thyroid hormone due to a novel thyroid hormone receptor mutant in a patient with hypothyroidism secondary to lingual thyroid and functional characterization of the mutant receptor.
  BACKGROUND: We describe a rare case of congenital hypothyroidism and an extremely high serum thyrotropin (TSH) level caused by a combination of resistance to thyroid hormone (RTH) and a lingual thyroid. As the RTH mutant, R316C, was new, the optimum dose of levothyroxine was unclear. To aid in assessment of the therapy, we characterized the mutant R316C thyroid hormone receptor (TR) and compared it with a common mutant, R316H, using in vitro studies. SUMMARY: The patient was a newborn female having severe hypothyroidism with a free thyroxine level of 0.36 ng/dL and a serum TSH level of 177 microU/mL. A scintiscan showed ectopic lingual thyroid tissue without a normal thyroid gland. Supplementation with levothyroxine at a dose of >350 microg/day did not normalize the serum TSH level; however, the patient showed normal growth and intelligence at 14 years of age. Consistent with the results of a computer analysis, the binding of R316C to triiodothyronine (T3) was significantly decreased to 38% that of the wild type. Electrophoretic mobility shift assay demonstrated that like R316H, R316C did not form a homodimer, but formed a heterodimer with RXR. However, a glutathione-S-transferase pull-down assay showed reduced binding of R316C with NCoR in the absence of T3 and impaired release in the presence of T3. In addition, transient transfection experiments demonstrated that unlike R316H, R316C had severe impairment of transcriptional activity on genes both positively and negatively regulated by thyroid hormone. It also had a clear dominant negative effect on genes negatively, but not positively, regulated by thyroid hormone, including the TSH-releasing hormone and TSHbeta genes. CONCLUSION: This is the first reported case of a R316C TR mutation. The characteristics of the R316C mutant differed from those of the R316H mutant. Our findings suggest that R316C causes reduced association with and impaired release of NCoR, resulting in RTH predominantly at the pituitary level, and that slightly elevated serum TSH level with high dose of levothyroxine might be optimum for normal growth.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T3 T4 T5 T6 T7 T8 T9
entities.type: CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-Y CHEMICAL GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: T3 TSH R316H R316C RXR R316C NCoR R316H R316C TSH-releasing hormone glutathione TSHbeta R316C TR R316C R316H R316C NCoR TSH R316C R316C S thyroid hormone receptor TR R316H TSH TSH thyrotropin R316C thyroid hormone receptor T3 T3 levothyroxine levothyroxine thyroxine levothyroxine triiodothyronine