Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a &lt;i&gt;TRβ&lt;/i&gt; Mutation

Wakasaki, Hisao; Matsumoto, Mutsuo; Tamaki, Shinya; Miyata, Kaori; Yamamoto, Shohei; Minaga, Takamasa; Hayashi, Yoshitaka; Komukai, Kenichi; Imanishi, Toshio; Yamaoka, Hiroyuki; Matsuno, Shohei; Nishi, Masahiro; Akamizu, Takashi

doi:10.2169/internalmedicine.55.7147

Cited by 6 publications

(6 citation statements)

References 28 publications

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“…As shown in Figure 4, treatment with roxadustat significantly induced the transcriptional activity of wild-type THRβ in Gal-4 driven reporter assays, to a lesser extent than that of T3. As expected, the native ligand T3 abolished or substantially diminished the transcriptional activity of four THRβ mutants associated with thyroid hormone resistance, V264D, H435L, R438H, and R438W, respectively (Wakasaki et al., 2016, Nomura et al., 1996, Sabet and Pallotta, 2011, Narumi et al., 2010). Surprisingly, the treatment of roxadustat either enhanced or retained the transcriptional activity of these THRβ mutants, all leading to higher induced transcriptional activity than those of T3 (Figure 4).…”

Section: Resultssupporting

confidence: 78%

Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance

et al. 2019

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SummaryResistance to thyroid hormone (RTH) is a clinical disorder without specific and effective therapeutic strategy, partly due to the lack of structural mechanisms for the defective ligand binding by mutated thyroid hormone receptors (THRs). We herein uncovered the prescription drug roxadustat as a novel THRβ-selective ligand with therapeutic potentials in treating RTH, thereby providing a small molecule tool enabling the first probe into the structural mechanisms of RTH. Despite a wide distribution of the receptor mutation sites, different THRβ mutants induce allosteric conformational modulation on the same His435 residue, which disrupts a critical hydrogen bond required for the binding of thyroid hormones. Interestingly, roxadustat retains hydrophobic interactions with THRβ via its unique phenyl extension, enabling the rescue of the activity of the THRβ mutants. Our study thus reveals a critical receptor allosterism mechanism for RTH by mutant THRβ, providing a new and viable therapeutic strategy for the treatment of RTH.

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Section: Resultssupporting

confidence: 78%

Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance

et al. 2019

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“…Finally, euthyroid individuals can show with increased serum hormone levels due to resistance to thyroid hormone mainly caused by mutations in the nuclear thyroid hormone receptor beta. In such cases, the increased serum hormone levels are due to reduced T3 binding to the receptor ( 20 – 23 ).…”

Section: Diagnosis Of and Differential Diagnosis To Fdh-t4mentioning

confidence: 99%

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

2017

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Familial dysalbuminemic hyperthyroxinemia (FDH-T4) and hypertriiodothyroninemia (FDH-T3) are dominantly inherited syndromes characterized by a high concentration of thyroid hormone in the blood stream. The syndromes do not cause disease, because the concentration of free hormone is normal, but affected individuals are at risk of erroneous treatment. FDH-T4 is the most common cause of euthyroid hyperthyroxinemia in Caucasian populations in which its prevalence is about 1 in 10,000 individuals, but the prevalence can be much higher in some ethnic groups. The condition is caused by a genetic variant of human serum albumin (HSA); Arg218 is mutated to histidine, proline, or serine or Arg222 is changed to isoleucine. The disorder is characterized by greater elevation in serum l-thyroxine (T4) than in serum triiodothyronine (T3); T4 can be increased by a factor 8–15. The high serum concentration of T4 is due to modification of a binding site located in the N-terminal half of HSA (in subdomain IIA). Thus, mutating Arg218 or Arg222 for a smaller amino acid reduces the steric restrictions in the site and creates a high-affinity binding site. The mutations can also affect binding of other ligands and can perhaps cause modified pharmacokinetics of albumin-binding drugs. In normal HSA, the high-affinity site has another location (in subdomain IIIB). Different locations of these sites imply that persons with and without FDH-T4 can have different types of interactions, and thereby complications, when given albumin-binding drugs. FDH-T3 is caused by a leucine to proline mutation in position 66 of HSA, which results in a large increment of the binding affinity for T3 but not for T4. For avoiding unwanted treatment of euthyroid persons with hyperthyroxinemia or hypertriiodothyroninemia, protein sequencing and/or sequencing of the albumin gene should be performed.

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“…Thyroid hormone receptors are encoded by 2 genes (THRα and THRβ), and THRS is usually caused by mutations in THRβ. [ 3 , 4 ] The majority of the mutations are located in 3 clusters enriched with CpG dinucleotide hot spots in the carboxy terminus of THRβ. [ 5 ] The THRβ gene contains 10 exons and encodes a total of 461 amino acids.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone resistance syndrome with P453T mutation in thyroid hormone receptor β gene

2020

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Rationale: Thyroid hormone resistance syndrome (THRS) is an inherited condition characterized by reduced responsiveness of target tissues to thyroid hormone. Due to their nonspecific symptomatic manifestations, these patients can be misdiagnosed. This study reports a pedigree with THRS caused by a mutation in the thyroid hormone receptor β (THRβ) gene. Patient concern: The proband, a 36-year-old woman at 19+4 weeks of gestation, was referred to our hospital because of abnormal thyroid function results. She was diagnosed with hyperthyroidism in October 2015, and had been treated with methimazole until her pregnancy. Diagnosis: The proband and 2 of her children were diagnosed with THRS based on genetic analysis. Sequence analysis of the THRβ gene showed a heterozygous mutation C>A located at exon 10. The mutation results in a change in proline for threonine at amino acid position 453, P453T. Interventions: No treatment will fully and specifically correct the defect. All 3 patients were in normal metabolic status, and thus treatment was not required. Outcomes: During a 2-year follow-up period, none of them had any complaints. The 20-year-old son (167 cm in height) and the 18-year-old daughter (150 cm in height) both had low academic performance. Lessons: Elevated serum thyroid hormone (TH) levels associated with nonsuppressed thyroid-stimulating hormone (TSH) levels usually leads to the diagnosis of THRS. Genetic analysis provides a short cut to diagnosis and the treatment should be based on the patient's clinical manifestations.

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Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a <i>TRβ</i> Mutation

Cited by 6 publications

References 28 publications

Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance

Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

Thyroid hormone resistance syndrome with P453T mutation in thyroid hormone receptor β gene

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