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Resistance to thyroid hormone induced tachycardia in RTHα syndrome

Dore, Riccardo ; Watson, Laura ; Hollidge, Stefanie ; Krause, Christin ; Sentis, Sarah Christine ; Oelkrug, Rebecca ; Geißler, Cathleen ; Johann, Kornelia ; Pedaran, Mehdi and Lyons, Greta , et al. (2023) In Nature Communications 14(1).
Abstract

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to... (More)

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
article number
3312
publisher
Nature Publishing Group
external identifiers
  • pmid:37286550
  • scopus:85161046020
ISSN
2041-1723
DOI
10.1038/s41467-023-38960-1
language
English
LU publication?
yes
id
e47370ac-5f40-4716-8100-506bb6eb7e24
date added to LUP
2023-08-15 15:08:05
date last changed
2024-04-20 01:41:30
@article{e47370ac-5f40-4716-8100-506bb6eb7e24,
  abstract     = {{<p>Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.</p>}},
  author       = {{Dore, Riccardo and Watson, Laura and Hollidge, Stefanie and Krause, Christin and Sentis, Sarah Christine and Oelkrug, Rebecca and Geißler, Cathleen and Johann, Kornelia and Pedaran, Mehdi and Lyons, Greta and Lopez-Alcantara, Nuria and Resch, Julia and Sayk, Friedhelm and Iwen, Karl Alexander and Franke, Andre and Boysen, Teide Jens and Dalley, Jeffrey W. and Lorenz, Kristina and Moran, Carla and Rennie, Kirsten L. and Arner, Anders and Kirchner, Henriette and Chatterjee, Krishna and Mittag, Jens}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Resistance to thyroid hormone induced tachycardia in RTHα syndrome}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-38960-1}},
  doi          = {{10.1038/s41467-023-38960-1}},
  volume       = {{14}},
  year         = {{2023}},
}