Clinical Phenotype and Mutant TRα1

Mullem, Alies van Mol-van; Heerebeek, Ramona van; Chrysis, Dionisios; Visser, Edward; Medici, Marco; Andrikoula, Maria; Tsatsoulis, Agathocles; Peeters, Robin P.; Visser, Theo J.

doi:10.1056/nejmc1113940

Cited by 191 publications

(155 citation statements)

References 5 publications

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“…Several types of patients with genetic defects in thyroid hormone signaling have been identified during the past decade, including those with mutations in thyroid hormone transporters (38) and receptors (14,39). In mice and humans, these defects often result in strongly impaired brain function.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Mittag¹,

Lyons²,

Sällström³

et al. 2012

J. Clin. Invest.

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Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone's central control of metabolism have been identified, its actions in the central cardiovascular control have remained enigmatic. Here, we describe a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus that requires thyroid hormone receptor signaling for proper development. Specific stereotaxic ablation of these cells in the mouse resulted in hypertension and temperature-dependent tachycardia, indicating a role in the central autonomic control of blood pressure and heart rate. Moreover, the neurons exhibited intrinsic temperature sensitivity in patch-clamping experiments, providing a new connection between cardiovascular function and core temperature. Thus, the data identify what we believe to be a novel hypothalamic cell population potentially important for understanding hypertension and indicate developmental hypothyroidism as an epigenetic risk factor for cardiovascular disorders. Furthermore, the findings may be beneficial for treatment of the recently identified patients that have a mutation in thyroid hormone receptor α1. IntroductionThyroid hormone is a well-known regulator of cardiovascular function and metabolic rate (1, 2). Hyperthyroid patients display increased metabolic rate and weight loss, despite increased food intake, as well as a profound tachycardia (2). Conversely, hypothyroid patients often suffer from weight gain and bradycardia (3). While most of the cardiovascular and metabolic effects of thyroid hormone have been attributed to direct actions in the corresponding peripheral tissues, such as heart (4) or skeletal muscle and fat (5, 6), recent studies have demonstrated that the hormone modulates these processes also through the brain (7): injections of thyroid hormone into different brain regions stimulate energy expenditure (8), and thyroid hormone signaling is required to establish the metabolic set point during embryonal development (9, 10).Similarly, thyroid hormone signaling is needed for the central modulation of heart rate. Mice that are heterozygous for a point mutation in thyroid hormone receptor α1 (Thra1 +/m ), which reduces the affinity to the ligand 10 fold (11), were unable to mount a correct cardiovascular response to stress, activity, or changes in environmental temperature due to a defective autonomous nervous system (12). While progress has been made in unraveling the molecular mechanisms of action of thyroid hormone in the central metabolic control and the identification of the underlying neuroanatomical areas (13), little is known about the anatomical substrates that mediate the effects of thyroid hormone on cardiovascular function.Here, we show that Thra1 +/m mice exhibit fewer parvalbuminergic neurons in a previously unknown population in the ant...

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Section: Discussionmentioning

confidence: 99%

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Mittag¹,

Lyons²,

Sällström³

et al. 2012

J. Clin. Invest.

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“…The human syndrome of resistance to thyroid hormone is typically caused by heterozygous coding mutations in the THRB gene that generate dominant negative proteins with little or no response to T 3 (458). Recently, similar mutations in the human THRA gene have been identified that generate dominant negative TRa1 proteins (459,460). The Thrb and Thra knockin mouse models display a range of tissueselective phenotypes and offer the opportunity to investigate the cellular and molecular defects underlying the disease symptoms in specific tissues (456,(461)(462)(463)(464)(465).…”

Section: And Recommendation 41bmentioning

confidence: 99%

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

174

106

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“…Although introducing a mutation in the mouse Thrb gene can alter cerebellum development (Portella et al, 2010), we previously found that all features of congenital hypothyroidism can be phenocopied by a Thra knock-in mutation, introducing the TRα1 L400R amino-acid substitution (Quignodon et al, 2007b;Fauquier et al, 2011). Accordingly, the first germline mutations of the human THRA gene, which were recently reported, caused a significant cognitive impairment (Bochukova et al, 2012;van Mullem et al, 2012) and supported a major role for TRα1 in the regulation of neurodevelopment by thyroid hormone.…”

Section: Introductionmentioning

confidence: 99%

Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development

et al. 2014

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Thyroid hormone is necessary for normal development of the central nervous system, as shown by the severe mental retardation syndrome affecting hypothyroid patients with low levels of active thyroid hormone. The postnatal defects observed in hypothyroid mouse cerebellum are recapitulated in mice heterozygous for a dominant-negative mutation of Thra, the gene encoding the ubiquitous TRα1 receptor. Using CRE/loxP-mediated conditional expression approach, we found that this mutation primarily alters the differentiation of Purkinje cells and Bergmann glia, two cerebellumspecific cell types. These primary defects indirectly affect cerebellum development in a global manner. Notably, the inward migration and terminal differentiation of granule cell precursors is impaired. Therefore, despite the broad distribution of its receptors, thyroid hormone targets few cell types that exert a predominant role in the network of cellular interactions that govern normal cerebellum maturation.

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Clinical Phenotype and Mutant TRα1

Cited by 191 publications

References 5 publications

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development

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