A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo.
Resistance to thyroid hormone (RTH) is most often due to point mutations in the beta-isoform of the thyroid hormone (TH) receptor (TR-beta). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-beta locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T(3) replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T(3) treatment failed to normally suppress these levels. T(3) treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T(3) treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.
Machado
Danielle S
DS
Department of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sabet
Amin
A
Santiago
Leticia A
LA
Sidhaye
Aniket R
AR
Chiamolera
Maria I
MI
Ortiga-Carvalho
Tania M
TM
Wondisford
Fredric E
FE
D000818:Animals; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D012097:Repressor Proteins / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics* / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*
D012097:Repressor Proteins; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine