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Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients
Open accessAbstract
BACKGROUND: The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2. METHODS: We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. FINDINGS: The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. INTERPRETATION: TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA. FUNDING: Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe.
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“Affected children and adults had a similar spectrum of abnormalities characteristic of the skeletal dysplasia and variable response to T4 treatment reported in individuals with mutations affecting TRα1 alone.”
From Thyroid diseases and bone health (2018) · cites this paper as [69]
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“In vitro analysis of the functional defects of mutant TRα1 proteins was also consistent with the phenotype–genotype correlation described above, while all studies showed that wild-type and mutant TRα2 proteins were transcriptionally inactive and had no dominant-negative activity [67, 69, 72, 76].”
From Thyroid diseases and bone health (2018) · cites this paper as [69]
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“Affected children and adults had a similar spectrum of abnormalities characteristic of the skeletal dysplasia and variable response to T4 treatment reported in individuals with mutations affecting TRα1 alone.”
From Thyroid diseases and bone health (2018) · cites this paper as [69]
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“More recently, THRA mutations affecting both TRα1 and TRα2 have been described [67, 69, 72, 76].”
From Thyroid diseases and bone health (2018) · cites this paper as [69]
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“In vitro analysis of the functional defects of mutant TRα1 proteins was also consistent with the phenotype–genotype correlation described above, while all studies showed that wild-type and mutant TRα2 proteins were transcriptionally inactive and had no dominant-negative activity [67, 69, 72, 76].”
From Thyroid diseases and bone health (2018) · cites this paper as [69]
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Cites
A Mutation in the Thyroid Hormone Receptor Alpha Gene
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Metadata
- Authors
- Moran, C., Agostini, M., Visser, W. E., Schoenmakers, E., Schoenmakers, N., Offiah, A. C., Poole, K., Rajanayagam, O., Lyons, G., Halsall, D., Gurnell, M., Chrysis, D., Efthymiadou, A., Buchanan, C., Aylwin, S., & Chatterjee, K. K.
- Affiliations
- University of Cambridge (GB)
- University of Sheffield (GB)
- Addenbrooke's Hospital (GB)
- University of Patras (GR)
- King's College Hospital (GB)
- ORCID
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 2
- Issue
- 8
- Pages
- 619-626
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC5989926
- OpenAlex
- W2090586265
- Cited by
- 127
- References
- 1
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 10 · 2022: 10 · 2021: 7 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 16 · 2016: 16 · 2015: 18 · 2014: 4
- FWCI
- 14.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (100574, 095564/Z/11/Z, 095564, 100585/Z/12/Z)
- National Institute for Health and Care Research (NF-SI-0508-10198)
- NIHR Cambridge Biomedical Research Centre
- 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 › Growth Hormone and Insulin-like Growth Factors
- Keywords
- thyroid hormone resistance, thyroid hormone receptor alpha 1, dominant negative inhibition, triiodothyronine, thyroxine therapy, growth failure, developmental delay, reverse T3
- MeSH terms
- Adult, Family Health, Female, Heterozygote, Humans, Male, Middle Aged, Polyps, Skin Neoplasms, Speech Disorders, Thyroxine, Treatment Outcome, Alternative Splicing, Thyroid Hormone Resistance Syndrome, Amino Acid Substitution, Protein Isoforms, Mutation, Missense, Gait Apraxia, Thyroid Hormone Receptors alpha, Megalencephaly
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