Embryonic Lethal Effect of Expressing a Dominant Negative Mutant Human Thyroid Hormone Receptor α1 in Mice

Abstract A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1PV/+ mice express a similar potent dominant-negative mutant TRα1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1PV/+ mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1PV/+ mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRα1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.

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Connexin40 Messenger Ribonucleic Acid Is Positively Regulated by Thyroid Hormone (TH) Acting in Cardiac Atria via the TH Receptor

Endocrinology ◽

10.1210/en.2008-0451 ◽

2008 ◽

Vol 150 (1) ◽

pp. 546-554 ◽

Cited By ~ 13

Author(s):

Norma A. S. Almeida ◽

Aline Cordeiro ◽

Danielle S. Machado ◽

Luana L. Souza ◽

Tânia M. Ortiga-Carvalho ◽

...

Keyword(s):

Thyroid Hormone ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Dominant Negative ◽

P Wave ◽

Dominant Negative Mutant ◽

Mrna Levels ◽

Messenger Ribonucleic Acid ◽

Wave Duration ◽

P Wave Duration

Thyroid hormone (TH) regulates many cardiac genes via nuclear thyroid receptors, and hyperthyroidism is frequently associated with atrial fibrillation. Electrical activity propagation in myocardium depends on the transfer of current at gap junctions, and connexins (Cxs) 40 and 43 are the predominant junction proteins. In mice, Cx40, the main Cx involved in atrial conduction, is restricted to the atria and fibers of the conduction system, which also express Cx43. We studied cardiac expression of Cx40 and Cx43 in conjunction with electrocardiogram studies in mice overexpressing the dominant negative mutant thyroid hormone receptor-β Δ337T exclusively in cardiomyocytes [myosin heavy chain (MHC-mutant)]. These mice develop the cardiac hypothyroid phenotype in the presence of normal serum TH. Expression was also examined in wild-type mice rendered hypothyroid or hyperthyroid by pharmacological treatment. Atrial Cx40 mRNA and protein levels were decreased (85 and 55%, respectively; P < 0.001) in MHC-mt mice. Atrial and ventricular Cx43 mRNA levels were not significantly changed. Hypothyroid and hyperthyroid animals showed a 25% decrease and 40% increase, respectively, in Cx40 mRNA abundance. However, MHC-mt mice presented very low Cx40 mRNA expression regardless of whether they were made hypothyroid or hyperthyroid. Atrial depolarization velocity, as represented by P wave duration in electrocardiograms of unanesthetized mice, was extremely reduced in MHC-mt mice, and to a lesser extent also in hypothyroid mice (90 and 30% increase in P wave duration). In contrast, this measure was increased in hyperthyroid mice (19% decrease in P wave duration). Therefore, this study reveals for the first time that Cx40 mRNA is up-regulated by TH acting in cardiac atria via the TH receptor and that this may be one of the mechanisms contributing to atrial conduction alterations in thyroid dysfunctions. Cardiac-specific expression of a mutant thyroid hormone receptor unable to bind thyroid hormone profoundly reduces atrial connexin 40 expression in association with prolonged atrial conduction.

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Two thyroid hormone response elements are present in the promoter of human thyroid hormone receptor beta 1.

Molecular Endocrinology ◽

10.1210/mend.8.3.8015548 ◽

1994 ◽

Vol 8 (3) ◽

pp. 305-314 ◽

Cited By ~ 1

Author(s):

S Suzuki ◽

T Miyamoto ◽

A Opsahl ◽

A Sakurai ◽

L J DeGroot

Keyword(s):

Thyroid Hormone ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Human Thyroid ◽

Hormone Response ◽

Response Elements ◽

Hormone Response Elements ◽

Receptor Beta

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Thyroid hormone receptor β mutations in the ‘hot-spot region’ are rare events in thyroid carcinomas

Journal of Endocrinology ◽

10.1677/joe-06-0009 ◽

2007 ◽

Vol 192 (1) ◽

pp. 83-86 ◽

Cited By ~ 12

Author(s):

Ana Sofia Rocha ◽

Ricardo Marques ◽

Inês Bento ◽

Ricardo Soares ◽

João Magalhães ◽

...

Keyword(s):

Thyroid Cancer ◽

Thyroid Hormone ◽

Transgenic Mice ◽

Cell Lines ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Hot Spot ◽

Direct Sequencing ◽

Human Thyroid ◽

Thyroid Hormone Receptor Β

Thyroid cancer constitutes the most frequent endocrine neoplasia. Targeted expression of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) and V600E V-raf murine sarcoma viral oncogene homolog B1 (BRAF) to the thyroid glands of transgenic mice results in tumours similar to those of human PTC, providing evidence for the involvement of these oncogenes in PTC. Kato et al. developed a mouse model that mimics the full spectrum of the human follicular form of thyroid cancer (FTC). FTC rapidly develops in these mice through introduction of the thyroid hormone receptor β (THRB)PV mutant on the background of the inactivated THRB wt locus. Our aim was to verify if, in the context of human follicular thyroid carcinogenesis, THRB acted as a tumour suppressor gene. We screened for mutations of the THRB gene in the hot-spot region, spanning exons 7–10, in 51 thyroid tumours and six thyroid cancer cell lines by PCR and direct sequencing. We did not find mutations in any of the tumours or cell lines analysed. Our findings suggest that, in contrast to the findings on the THRB-mutant transgenic mice, THRB gene mutations are not a relevant mechanism for human thyroid carcinogenesis.

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