Resistance to thyroid hormone induced tachycardia in RTHα syndrome

Riccardo Dore, Laura Watson, Stefanie Hollidge, Christin Krause, Sarah Christine Sentis, Rebecca Oelkrug, Cathleen Geißler, Kornelia Johann, Mehdi Pedaran, Greta Lyons, Nuria Lopez-Alcantara, Julia Resch, Friedhelm Sayk, Karl Alexander Iwen, Andre Franke, Teide Jens Boysen, Jeffrey W. Dalley, Kristina Lorenz, Carla Moran, Kirsten L. Rennie, Anders Arner, Henriette Kirchner, Krishna Chatterjee and Jens Mittag ()
Additional contact information
Riccardo Dore: University of Lübeck
Laura Watson: National Institute Health and Care Research Cambridge Clinical Research Facility, Addenbrooke’s Hospital
Stefanie Hollidge: University of Cambridge
Christin Krause: University of Lübeck
Sarah Christine Sentis: University of Lübeck
Rebecca Oelkrug: University of Lübeck
Cathleen Geißler: University of Lübeck
Kornelia Johann: University of Lübeck
Mehdi Pedaran: University of Lübeck
Greta Lyons: University of Cambridge
Nuria Lopez-Alcantara: University of Lübeck
Julia Resch: University of Lübeck
Friedhelm Sayk: Internal Medicine I, Universitätsklinikum Schleswig-Holstein
Karl Alexander Iwen: University of Lübeck
Andre Franke: Christian-Albrechts-University of Kiel
Teide Jens Boysen: Christian-Albrechts-University of Kiel
Jeffrey W. Dalley: University of Cambridge
Kristina Lorenz: University of Würzburg
Carla Moran: University of Cambridge
Kirsten L. Rennie: University of Cambridge
Anders Arner: Lund University
Henriette Kirchner: University of Lübeck
Krishna Chatterjee: University of Cambridge
Jens Mittag: University of Lübeck

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41467-023-38960-1

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