A Mutation in the Thyroid Hormone Receptor Alpha Gene

Bochukova, Elena G.; Schoenmakers, Nadia; Agostini, Maura; Schoenmakers, Erik; Rajanayagam, Odelia; Keogh, Julia M.; Henning, Elana; Reinemund, Jana; Gevers, Evelien; Sarri, Margarita; Downes, Kate; Offiah, A.C.; Albanese, Assunta; Halsall, David; Schwabe, John W. R.; Bain, Murray D.; Lindley, Keith; Muntoni, F.; Vargha‐Khadem, Faraneh; Khadem, Faraneh Vargha; Dattani, Mehul; Farooqi, I. Sadaf; Gurnell, Mark; Chatterjee, Krishna

doi:10.1056/nejmoa1110296

Cited by 348 publications

(333 citation statements)

References 23 publications

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“…The hypotension observed in the recently identified patient with a mutant thyroid hormone receptor α1 (TRα1) allele (14) prompted us to investigate blood pressure and associated serum parameters in our Thra1 +/m animal model. Surprisingly, despite strongly reduced pulmonary angiotensin-converting enzyme (Ace) expression and lower serum angiotensin II levels in the mutant animals ( Figure 1A), we found that blood pressure was similar to that in wild-type controls ( Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

“…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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“…In vitro studies of these human mutations further support the genetic evidence. Both the E403× TRα1 mutant described by Bochukova et al (10) and the E397fs406× TRα1 mutant described by van Mullem et al (11) act in a dominant negative fashion to interfere with the transcription activity of WT TRs. In vitro studies further show that the E403× TRα1 mutant is defective in its ability to release corepressors in the presence of T3 (10).…”

Section: Discussionmentioning

confidence: 99%

“…Others have also shown that mutations of the Thra gene in mice lead to phenotypes distinct from those of mice with knockin mutations of the Thrb gene (7)(8)(9). However, these mouse genetic findings showing that mutations of the Thra gene are not embryonic lethal, but have phenotypes differ from mutations of the Thrb gene, were not verified in humans until recently when patients were found with mutations of the THRA gene (10,11). Indeed, TRα1PV shares the same mutated C-terminal sequence (-TLPRGL) with truncated termination at amino acid L406 as those of two patients with frameshift mutations of the THRA gene (11).…”

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confidence: 99%

Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

Fozzatti

Kim

Park

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Genetic evidence from patients with mutations of the thyroid hormone receptor α gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRα1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TRα1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1 PV mice, expressing a dominant negative TRα1 mutant (TRα1PV), with mice expressing a mutant Ncor1 allele (Ncor1 ΔID mice) that cannot recruit the TR or PV mutant. TRα1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1ΔID ameliorated abnormalities in the thyroid-pituitary axis of Thra1 PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1 PV/+ mice expressing NCOR1ΔID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor γ and CCAAT/enhancerbinding protein α gene, due to the inability of TRα1PV to recruit NCOR1ΔID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TRα1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRα1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRα1 mutant-mediated hypothyroidism in patients.growth retardation | lipid metabolism | fertility defect T he thyroid hormone T3 regulates growth and development and maintains metabolic homeostasis in humans. The genomic signaling by T3 is via the thyroid hormone receptor (TR) isoforms α1, β1, and β2, which are encoded by the THRA and THRB genes located on two different chromosomes. These TR isoforms share extensive sequence homology in the DNA and T3 binding domains but differ in the amino terminal A/B domains (1). TR binds to the thyroid hormone response elements (TREs) and recruits nuclear coregulatory proteins to regulate gene transcription. In the absence of T3, TRs recruit the nuclear corepressors (NCOR1 and NCOR2) for transcriptional repression on the T3 positively regulated genes. In the presence of T3, the T3-bound TR undergoes structural changes, resulting in the release of corepressors, allowing recruitment of nuclear receptor coactivators (e.g., SRC-1) to facilitate transcription activation (2, 3).The critical roles of TR in mediating biological functions of T3 are clearly evident, in that mutations of the THRB gene cause resistance to thyroid hormone (RTH) (3). The intriguing observation that no mutations of the THRA gene were ever found in RTH patients raised the possibilities that mutations of the THRA gene could be embryonic lethal or could confer different clinical manifestations. These possibilities were explored by using a powerful mouse genetic approach. Targeting a ...

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“…By contrast, genetic data indicate that the two receptors have very different functions in vivo. Two germ-line mutations have been reported recently for the human Thra gene (14,15). The patients share typical symptoms of congenital hypothyroidism, including cognitive impairments.…”

mentioning

confidence: 99%

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

Chatonnet

Guyot

Galand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

109

100

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TRα1 and TRβ1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3′,5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRβ1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRβ1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.

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A Mutation in the Thyroid Hormone Receptor Alpha Gene

Cited by 348 publications

References 23 publications

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

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