A Point Mutation in the Activation Function 2 Domain of Thyroid Hormone Receptor α1 Expressed after CRE-Mediated Recombination Partially Recapitulates Hypothyroidism
Abstract
Thyroid hormones act directly on transcription by binding to TRalpha1, TRbeta1, and TRbeta2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely the implication of the widely expressed TRalpha1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRalpha1 coding sequence, which is expressed only after CRE/loxP-mediated DNA recombination. The amino acid change prevents interaction between TRalpha1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects postnatal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRbeta1 and TRbeta2 are predominantly expressed. Both respective abundance and intrinsic properties of TRalpha1 and TRbeta1/2 seem to govern specificity of action.
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Together, the reports define a new genetic disorder, RTHα, characterized by profound and consistent developmental abnormalities of the skeleton that recapitulate findings in mice with dominant-negative Thra mutations.
“Together, these reports define a new genetic disorder, RTHα, characterized by profound and consistent developmental abnormalities of the skeleton that recapitulate findings in mice with dominant-negative Thra mutations [80–85].”
From Thyroid diseases and bone health (2018) · cites this paper as [84]
Cites
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Role of Thyroid Hormones in Skeletal Development and Bone Maintenance
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Thyroid hormone receptors and resistance to thyroid hormone disorders
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A Mutation in the Thyroid Hormone Receptor Alpha Gene
Bochukova, E., Schoenmakers, N., Agostini, M., Schoenmakers, E., Rajanayagam, O., Keogh, J. M., Henning, E., Reinemund, J., Gevers, E., Sarri, M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1110296 · Cited by 379 · see citing works
Thyroid diseases and bone health
Williams, G. R., & Bassett, J. H. D. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0753-4 · Cited by 276 · see citing works
Central vs. Peripheral Action of Thyroid Hormone in Adaptive Thermogenesis: A Burning Topic
Zekri, Y., Flamant, F., & Gauthier, K. (2021) · Cells · doi:10.3390/cells10061327 · Cited by 27 · see citing works
Self-citationRole of Thyroid Hormone Receptor-α1 in Endochondral Ossification
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- Authors
- Quignodon, L., Vincent, S., Winter, H., Samarut, J., & Flamant, F.
- Affiliations
- Lyon 1 Université (FR)
- University of Tübingen (DE)
- ORCID
- Flamant, Frédéric
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-10
- Volume
- 21
- Issue
- 10
- Pages
- 2350-2360
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2149885497
- Cited by
- 106
- References
- 1
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 9 · 2015: 6 · 2014: 10 · 2013: 6 · 2012: 10
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- thyroid hormone receptor alpha 1, dominant negative receptor, hypothyroidism, Cre-loxP recombination, transgenic mice, thyroid hormone receptor beta 1, TRbeta2, receptor specificity, postnatal development, thyroid hormone action
- MeSH terms
- Alleles, Animals, Arginine, Bone and Bones, Genes, Dominant, Hypothyroidism, Leucine, Mice, Transgenic, Recombination, Genetic, Tamoxifen, Point Mutation, Integrases, Amino Acid Substitution, Thyroid Hormone Receptors alpha, Thyroid Hormone Receptors beta, Mice
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