One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction

Narumi, Shunji; Cho, Hideo; Tamada, Izumi; Kozu, Yuki; Tsuchiya, Takayoshi; Nagai, Toshiro; Hasegawa, Tomonobu

doi:10.1297/cpe.19.91

Cited by 7 publications

(9 citation statements)

References 16 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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Section: Discussionmentioning

confidence: 52%

“…this variant appears to have been reported in a case report of a french patient with thyroid hormone resistance [ 12 ]. It was also reported in another affected individual but was inherited from an apparently unaffected father [ 11 ]. Another variant affecting the same amino acid has also been reported in a patient with thyroid hormone resistance [ 13 ].…”

Section: Discussionmentioning

confidence: 91%

“…To date, more than 100 THRB mutations have been reported among RTH patients. Most mutations substitute a single amino-acid residue in the ligand-binding domain [ 11 ]. The most unique part of our case is found in the genetic study, which confirmed that the patient is heterozygous in THRb gene for sequence variant designated c.1147C>T, which is predicted to result in amino acid substitution p.Arg383Cys.…”

Section: Discussionmentioning

confidence: 99%

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Case of Resistance to Thyroid Hormones With a Relatively Rare Mutation in Thyroid Hormones Receptor

Ahmed

Hassan

Ahmed

2021

Cureus

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Normal thyroid hormone level is essential to maintain the normal physiologic function of the human body. Disturbances of these hormone levels have variable clinical manifestations ranging from asymptomatic to severe illness. Resistance to thyroid hormone (RTH) is a syndrome characterized by reduced intracellular action of T3, the active thyroid hormone. It is a rare autosomal dominant condition and occurs mostly due to heterogeneous mutations in the thyroid hormone receptor. Other causes of RTH include thyroid hormone cell membrane transport defect and thyroid hormone metabolism defect. Affected individuals present with symptoms of both increased and decreased thyroid hormone action, depending on the tissue's predominant receptor isoform expression, the magnitude of hormonal resistance, and the effectiveness of compensatory mechanisms.Here, we share our experience in diagnosing a case of RTH confirmed with a genetic test and found to have sequence variant mutation that is not well described in the literature previously due to the absence of genetic conclusive evidence.

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“…Heterozygous p.R383C mutation showing dominant negative eff ect has been reported in both GRTH and PRTH cases [ 9 ] . In context of our investigation, it is noteworthy that the p.R383C mutation has been also predicted to loose hydrogen bonds between R383 and E311 [ 9 ] . p.R429Q is a common mutation usually associated with a clinically apparent pituitary resistance phenotype (PRTH) [ 2 ] .…”

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confidence: 99%

A Novel p.E311K Mutation of Thyroid Receptor Beta Gene in Resistance to Thyroid Hormone Syndrome, Inherited in Autosomal Recessive Trait

et al. 2012

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Resistance to thyroid hormone (RTH) syndrome is caused by mutations in THRB gene and is inherited mainly as an autosomal dominant trait with dominant negative effect. Most of up-to-now described RTH cases were heterozygous. We studied a 19-year-old woman presenting severe mental impairment, hyperkinetic behavior, learning disability, hearing loss, tachycardia, goiter, strabismus, nystagmus, and normal stature. The laboratory findings revealed elevated TSH, T3, and T4 serum levels. Her parents were healthy with normal serum level of TSH, fT3, and fT4. Sequence based prediction of a substitution was analyzed by SDM, PolPhen, and SNAP software whereas structural visualizations were performed in UCSF Chimera. We found a novel mutation in THRB gene in position 1216 (G to A transition, codon 311) resulting in novel Glu-311-Lys (p.E311K) substitution, homozygous in proband presenting with severe symptoms of RTH and heterozygous in both of her healthy parents, thus suggesting autosomal recessive mode of inheritance. p.E311K substitution was not found in 50 healthy, unrelated individuals. p.E311K was shown to be deleterious by SDM, PolPhen, and SNAP software. Structural visualizations of mutated protein performed by UCSF Chimera software disclosed a loss of hydrogen bonds between E311, R383, and R429 along with abnormal residue-residue contact between K311 and L377. This is a very rare case of a homozygous mutation in a patient with severe symptoms of RTH and lack of symptoms in both heterozygous parents. Although, computational analyses have provided the evidence that p.E311K substitution may affect THRB function, lack of dominant negative effect typical for THRB mutations could not be explained by structure-based modeling. Further in vitro analysis is required to assess the functional consequences of this substitution.

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One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction

Cited by 7 publications

References 16 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

Case of Resistance to Thyroid Hormones With a Relatively Rare Mutation in Thyroid Hormones Receptor

A Novel p.E311K Mutation of Thyroid Receptor Beta Gene in Resistance to Thyroid Hormone Syndrome, Inherited in Autosomal Recessive Trait

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