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 Dalley; Kristina Lorenz; Carla Moran; Kirsten L. Rennie; Anders Arner; Henriette Kirchner; Vengalil 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 Dalley, Kristina Lorenz, Carla Moran, Kirsten L. RennieAnders Arner, Henriette Kirchner, Vengalil Krishna Chatterjee, Jens Mittag^*

^*Corresponding author for this work

University of Lübeck

Research output: Contribution to journal › Journal article › Research › peer-review

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
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-38960-1
Publication status	Published - 7. Jun 2023
Externally published	Yes

Keywords

Animals
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics
Male
Mice
Mutation
Tachycardia/genetics
Thyroid Hormone Receptors alpha/genetics
Thyroid Hormone Resistance Syndrome/genetics
Thyroid Hormones
Thyroxine/therapeutic use

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10.1038/s41467-023-38960-1Licence: CC BY

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., Lorenz, K., Moran, C., ... Mittag, J. (2023). Resistance to thyroid hormone induced tachycardia in RTHα syndrome. Nature Communications, 14, Article 3312. https://doi.org/10.1038/s41467-023-38960-1

@article{8c069c5fcfe94308a5004693891ae96c,

title = "Resistance to thyroid hormone induced tachycardia in RTHα syndrome",

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.",

keywords = "Animals, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics, Male, Mice, Mutation, Tachycardia/genetics, Thyroid Hormone Receptors alpha/genetics, Thyroid Hormone Resistance Syndrome/genetics, Thyroid Hormones, Thyroxine/therapeutic use",

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 Jeffrey Dalley and Kristina Lorenz and Carla Moran and Rennie, {Kirsten L.} and Anders Arner and Henriette Kirchner and Chatterjee, {Vengalil Krishna} and Jens Mittag",

year = "2023",

month = jun,

day = "7",

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

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, J, Lorenz, K, Moran, C, Rennie, KL, Arner, A, Kirchner, H, Chatterjee, VK & Mittag, J 2023, 'Resistance to thyroid hormone induced tachycardia in RTHα syndrome', Nature Communications, vol. 14, 3312. https://doi.org/10.1038/s41467-023-38960-1

TY - JOUR

T1 - Resistance to thyroid hormone induced tachycardia in RTHα syndrome

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

AU - Lorenz, Kristina

AU - Moran, Carla

AU - Rennie, Kirsten L.

AU - Arner, Anders

AU - Kirchner, Henriette

AU - Chatterjee, Vengalil Krishna

AU - Mittag, Jens

PY - 2023/6/7

Y1 - 2023/6/7

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.

KW - Animals

KW - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics

KW - Male

KW - Mice

KW - Mutation

KW - Tachycardia/genetics

KW - Thyroid Hormone Receptors alpha/genetics

KW - Thyroid Hormone Resistance Syndrome/genetics

KW - Thyroid Hormones

KW - Thyroxine/therapeutic use

U2 - 10.1038/s41467-023-38960-1

DO - 10.1038/s41467-023-38960-1

M3 - Journal article

C2 - 37286550

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 3312

ER -

Resistance to thyroid hormone induced tachycardia in RTHα syndrome

Abstract

Keywords

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