PMID- 31530256
OWN - NLM
STAT- MEDLINE
DCOM- 20201026
LR  - 20201026
IS  - 1557-9077 (Electronic)
IS  - 1050-7256 (Linking)
VI  - 29
IP  - 12
DP  - 2019 Dec
TI  - The In Vitro Functional Impairment of Thyroid Hormone Receptor Alpha 1 Isoform 
      Mutants Is Mainly Dictated by Reduced Ligand Sensitivity.
PG  - 1834-1842
LID - 10.1089/thy.2019.0019 [doi]
AB  - Background: Thyroid hormone (TH) acts on TH receptors (TRs) and regulates gene 
      transcription by binding of TRs to TH response elements (TREs) in target gene 
      promoters. The transcriptional activity of TRs is modulated by interactions with 
      TR-coregulatory proteins. Mutations in TRalpha cause resistance to thyroid hormone 
      alpha (RTHalpha). In this study, we analyzed if, beyond reduced triiodothyronine (T3) 
      affinity, altered interactions with cofactors or different TREs could account for 
      the differential impaired transcriptional activity of different mutants. Methods: 
      We evaluated four mutants derived from patients (D211G, M256T, A263S, and R384H) 
      and three artificial mutants at equivalent positions in patients with RTHbeta 
      (T223A, L287V, and P398H). The in vitro transcriptional activity was evaluated on 
      TRE-luciferase reporters (DR4, IR0, and ER6). The affinity for T3 and interaction 
      with coregulatory proteins (nuclear receptor corepressor 1 [NCoR1] and steroid 
      receptor coactivator 1 [SRC1]) were also determined. Results: We found that the 
      affinity for T3 was significantly reduced for all mutants, except for TRalpha1-T223A. 
      The reduction in the T3 sensitivity of the transcriptional activity on three 
      TREs, the dissociation of the corepressor NCoR1, and the association of the 
      coactivator SRC1 recruitment for each mutant correlated with the reduced affinity 
      for T3. We did not observe mutation-specific alterations in interactions with 
      cofactors or TREs. Conclusions: In summary, the degree of impaired 
      transcriptional activity of mutants is mainly determined by their reduced 
      affinity for T3.
FAU - Wejaphikul, Karn
AU  - Wejaphikul K
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
AD  - Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, 
      Thailand.
FAU - van Gucht, Anja L M
AU  - van Gucht ALM
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
FAU - Groeneweg, Stefan
AU  - Groeneweg S
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
FAU - Visser, W Edward
AU  - Visser WE
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
FAU - Visser, Theo J
AU  - Visser TJ
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
FAU - Peeters, Robin P
AU  - Peeters RP
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
FAU - Meima, Marcel E
AU  - Meima ME
AD  - Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus 
      MC, Rotterdam, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191119
PL  - United States
TA  - Thyroid
JT  - Thyroid : official journal of the American Thyroid Association
JID - 9104317
RN  - 0 (Ligands)
RN  - 0 (NCOR1 protein, human)
RN  - 0 (Nuclear Receptor Co-Repressor 1)
RN  - 0 (Thyroid Hormone Receptors alpha)
RN  - 06LU7C9H1V (Triiodothyronine)
RN  - EC 2.3.1.48 (NCOA1 protein, human)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
SB  - IM
MH  - Cell Line, Tumor
MH  - Computer Simulation
MH  - Humans
MH  - Ligands
MH  - Models, Molecular
MH  - Mutation/*genetics
MH  - Nuclear Receptor Co-Repressor 1/genetics
MH  - Nuclear Receptor Coactivator 1/genetics
MH  - Protein Binding
MH  - Response Elements
MH  - Thyroid Hormone Receptors alpha/*genetics/*metabolism
MH  - Transcription, Genetic
MH  - Triiodothyronine/metabolism
OTO - NOTNLM
OT  - coregulatory proteins
OT  - receptor mutation
OT  - resistance to thyroid hormone
OT  - thyroid hormone action
OT  - thyroid hormone receptor
OT  - thyroid hormone response elements
EDAT- 2019/09/19 06:00
MHDA- 2020/10/27 06:00
CRDT- 2019/09/19 06:00
PHST- 2019/09/19 06:00 [pubmed]
PHST- 2020/10/27 06:00 [medline]
PHST- 2019/09/19 06:00 [entrez]
AID - 10.1089/thy.2019.0019 [doi]
PST - ppublish
SO  - Thyroid. 2019 Dec;29(12):1834-1842. doi: 10.1089/thy.2019.0019. Epub 2019 Nov 19.