Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta.
Open accessAbstract
The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. We have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine----cytosine replacement in the codon for amino acid 340 resulted in a glycine----arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor beta gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor beta gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule.
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Disruption of the HPT axis in RTHβ leads to a characteristic increase in TSH along with inappropriately normal or increased circulating T4 and T3 levels.
“RTHβ results from dominant-negative mutations of THRB that cause disruption of the HPT axis leading to a characteristic increase in TSH along with inappropriately normal or increased circulating T4 and T3 levels [86–88].”
From Thyroid diseases and bone health (2018) · cites this paper as [88]
The Abstract (page not specified in our copy) links generalized thyroid hormone resistance to a mutation in one THRB allele and describes elevated circulating thyroid hormone. It does not report a characteristic increase in TSH, normal T4 or T3 levels, or a dominant-negative mechanism. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRTHβ results from dominant-negative mutations of THRB.
“RTHβ results from dominant-negative mutations of THRB that cause disruption of the HPT axis leading to a characteristic increase in TSH along with inappropriately normal or increased circulating T4 and T3 levels [86–88].”
From Thyroid diseases and bone health (2018) · cites this paper as [88]
The indexed Abstract reports an inherited case of thyroid hormone resistance with a mutation in one of two thyroid hormone receptor beta gene alleles; the mutant receptor did not bind triiodothyronine. It does not establish that the mutation inhibits the normal receptor—the dominant-negative mechanism attributed to it. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDominant-negative mutations of THRB cause disruption of the HPT axis.
“RTHβ results from dominant-negative mutations of THRB that cause disruption of the HPT axis leading to a characteristic increase in TSH along with inappropriately normal or increased circulating T4 and T3 levels [86–88].”
From Thyroid diseases and bone health (2018) · cites this paper as [88]
The Abstract (page not specified in our copy) reports an inherited thyroid-hormone-resistance syndrome associated with a mutation in one allele of the thyroid hormone receptor beta gene. It does not establish that the mutation acts through a dominant-negative mechanism or show disruption of the HPT axis. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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- Authors
- Sakurai, A., Takeda, K., Ain, K., Ceccarelli, P., Nakai, A., Seino, S., Bell, G. I., Refetoff, S., & DeGroot, L. J.
- Affiliations
- University of Chicago (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1989-11
- Volume
- 86
- Issue
- 22
- Pages
- 8977-8981
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC298414
- OpenAlex
- W1984214334
- Cited by
- 268
- References
- 0
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 6 · 2016: 3 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 7
- FWCI
- 14.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 13 377, DK 00055, DK27384)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- thyroid hormone resistance, thyroid hormone receptor beta, ligand-binding domain, triiodothyronine binding, thyroid hormone nuclear receptors, point mutations, family studies
- MeSH terms
- Alleles, Base Sequence, Binding Sites, Child, Drug Resistance, Exons, Female, Genes, Humans, Introns, Ligands, Male, Molecular Sequence Data, Mutation, Receptors, Thyroid Hormone, Thyroid Diseases, Thyrotropin, Thyroxine, Thyroxine-Binding Proteins, Triiodothyronine
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