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. RennieAnders Arner, Henriette Kirchner, Krishna Chatterjee, Jens Mittag*

*Korrespondierende/r Autor/-in für diese Arbeit
3 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummer3312
ZeitschriftNature Communications
Jahrgang14
Ausgabenummer1
Seiten (von - bis)3312
ISSN1751-8628
DOIs
PublikationsstatusVeröffentlicht - 12.2023

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

DFG-Fachsystematik

  • 205-17 Endokrinologie, Diabetologie, Metabolismus

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