A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition.
Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary in association with abnormal peripheral tissue responses to thyroid hormone. Whether TR-beta mutations cause a selective form of RTH, which only leads to abnormal pituitary TSH secretion (PRTH), is unclear. In a patient with PRTH, a novel mutation of a conserved arginine residue adjacent to the ninth heptad of TR-beta selectively disrupts TR homodimer formation. The mutant TR displays normal or enhanced function on stimulatory thyroid hormone response elements found in peripheral tissues, but has defective function on inhibitory thyroid hormone response elements found in the TRH and TSH subunit genes and explains the PRTH phenotype. This is the first report of a mutation in a member of the nuclear receptor superfamily that selectively abolishes hormone-dependent inhibition and localizes a novel C-terminal domain necessary for this property.
Flynn
T R
TR
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.
Hollenberg
A N
AN
Cohen
O
O
Menke
J B
JB
Usala
S J
SJ
Tollin
S
S
Hegarty
M K
MK
Wondisford
F E
FE
D000595:Amino Acid Sequence; D013956:Antithyroid Agents; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013972:Thyrotropin / Q000378:metabolism
D013956:Antithyroid Agents; D009838:Oligodeoxyribonucleotides; D011988:Receptors, Thyroid Hormone; D013972:Thyrotropin; D001120:Arginine