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PMID: 11274423 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

An unliganded thyroid hormone receptor causes severe neurological dysfunction.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 7 ·2001-03-27 ·Pages 3998-4003

Hashimoto K, Curty FH, Borges PP, Lee CE, Abel ED, Elmquist JK, Cohen RN, Wondisford FE

Abstract

Congenital hypothyroidism and the thyroid hormone (T(3)) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a T(3) binding mutation was introduced into the mouse TR-beta locus by homologous recombination. Because of this T(3) binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.

MeSH Terms
Animals Cerebellar Diseases/etiology,metabolism,physiopathology Hypothalamus/metabolism Hypothyroidism/complications,genetics,metabolism Learning Disabilities/etiology,metabolism Mice Mice, Knockout Pituitary-Adrenal System/metabolism Receptors, Thyroid Hormone/deficiency,genetics,metabolism Thyroid Gland/metabolism
Chemicals
Receptors, Thyroid Hormone
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hashimoto K
Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Curty F H
Borges P P
Lee C E
Abel E D
Elmquist J K
Cohen R N
Wondisford F E
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.051454698
Published
2001-03-27
Epub
2001-00-06
Pages
3998-4003
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC31168
Subset
IM
Grants
NIDDK NIH HHS · R01 DK049126 · United States
NIDDK NIH HHS · R01 DK053036 · United States
NIDDK NIH HHS · DK 49126 · United States
NIDDK NIH HHS · DK 53036 · United States
External Links
PubMed source DOI: 10.1073/pnas.051454698 PMC Full Text View journal details
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