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; Jens Mittag

doi:10.1038/s41467-023-38960-1

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^*

^*Corresponding author for this work

17 Citations (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.

Original language	English
Article number	3312
Journal	Nature Communications
Volume	14
Issue number	1
Pages (from-to)	3312
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-023-38960-1
Publication status	Published - 12.2023

Funding

We thank the Gemeinsame Tierhaltung Lübeck for excellent animal caretaking. Research in human participants is supported by the Wellcome Trust (Investigator Award 210755/Z/18/Z to K.C.) and NIHR Cambridge Biomedical Research Centre (to K.C., C.M., G.L.) and was conducted in the NIHR Cambridge Clinical Research Facility. S.H. and K.L.R. were also supported by the NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014). We are grateful for funding from the German Research Council DFG in the framework of CRC/TR296 “LocoTact” (funding ID 424957847 to J.M.), GRK1957 “Adipocyte Brain Crosstalk” to J.M., MI1242/3-2 to J.M. and OE723/2-1 (funding ID 434396546 to R.O.). We also thank Prof. Ursula Ravens for constructive criticism on our manuscript.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.22-17 Endocrinology, Diabetology, Metabolism

Access to Document

10.1038/s41467-023-38960-1

Cite this

Dore, R., Watson, L., Hollidge, S., Krause, C., Sentis, S. C., Oelkrug, R., Geißler, C., Johann, K., Pedaran, M., Lyons, G., Lopez-Alcantara, N., Resch, J., Sayk, F., Iwen, K. A., Franke, A., Boysen, T. J., Dalley, J. W., Lorenz, K., Moran, C., ... Mittag, J. (2023). Resistance to thyroid hormone induced tachycardia in RTHα syndrome. Nature Communications, 14(1), 3312. Article 3312. https://doi.org/10.1038/s41467-023-38960-1

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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.",

author = "Riccardo Dore and Laura Watson and Stefanie Hollidge and Christin Krause and Sentis, \{Sarah Christine\} and Rebecca Oelkrug and Cathleen Gei{\ss}ler and Kornelia Johann and Mehdi Pedaran and Greta Lyons and Nuria Lopez-Alcantara and Julia Resch and Friedhelm Sayk and Iwen, \{Karl Alexander\} and Andre Franke and Boysen, \{Teide Jens\} and Dalley, \{Jeffrey W.\} and Kristina Lorenz and Carla Moran and Rennie, \{Kirsten L.\} and Anders Arner and Henriette Kirchner and Krishna Chatterjee and Jens Mittag",

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month = dec,

doi = "10.1038/s41467-023-38960-1",

language = "English",

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Dore, R, Watson, L, Hollidge, S, Krause, C, Sentis, SC, Oelkrug, R, Geißler, C, Johann, K, Pedaran, M, Lyons, G, Lopez-Alcantara, N, Resch, J, Sayk, F, Iwen, KA, Franke, A, Boysen, TJ, Dalley, JW, Lorenz, K, Moran, C, Rennie, KL, Arner, A, Kirchner, H, Chatterjee, K & Mittag, J 2023, 'Resistance to thyroid hormone induced tachycardia in RTHα syndrome', Nature Communications, vol. 14, no. 1, 3312, pp. 3312. https://doi.org/10.1038/s41467-023-38960-1

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AU - Dore, Riccardo

AU - Watson, Laura

AU - Hollidge, Stefanie

AU - Krause, Christin

AU - Sentis, Sarah Christine

AU - Oelkrug, Rebecca

AU - Geißler, Cathleen

AU - Johann, Kornelia

AU - Pedaran, Mehdi

AU - Lyons, Greta

AU - Lopez-Alcantara, Nuria

AU - Resch, Julia

AU - Sayk, Friedhelm

AU - Iwen, Karl Alexander

AU - Franke, Andre

AU - Boysen, Teide Jens

AU - Dalley, Jeffrey W.

AU - Lorenz, Kristina

AU - Moran, Carla

AU - Rennie, Kirsten L.

AU - Arner, Anders

AU - Kirchner, Henriette

AU - Chatterjee, Krishna

AU - Mittag, Jens

PY - 2023/12

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N2 - 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.

AB - 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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DO - 10.1038/s41467-023-38960-1

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AN - SCOPUS:85161046020

SN - 1751-8628

VL - 14

SP - 3312

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3312

ER -

Resistance to thyroid hormone induced tachycardia in RTHα syndrome

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

CRC/TRR 296 LocoTact: Local control of TH action

Cite this

Resistance to thyroid hormone induced tachycardia in RTHα syndrome

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

Projects

CRC/TRR 296 LocoTact: Local control of TH action

Cite this