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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; Lyons, Greta; Lopez-Alcantara, Nuria; Resch, Julia; Sayk, Friedhelm; Iwen, Karl Alexander; Franke, Andre; Boysen, Teide Jens; Dalley, Jeffrey W; Lorenz, Kristina; Moran, Carla; Rennie, Kirsten L; Arner, Anders; Kirchner, Henriette; Chatterjee, Krishna; Mittag, Jens.
Afiliação
  • Dore R; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Watson L; National Institute Health and Care Research Cambridge Clinical Research Facility, Addenbrooke's Hospital, Cambridge, UK.
  • Hollidge S; MRC Epidemiology Unit and Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Krause C; Institute for Human Genetics, Department of Epigenetics & Metabolism, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Sentis SC; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Oelkrug R; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Geißler C; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Johann K; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Pedaran M; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Lyons G; Wellcome-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
  • Lopez-Alcantara N; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Resch J; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Sayk F; Internal Medicine I, Universitätsklinikum Schleswig-Holstein, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Iwen KA; Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Franke A; Internal Medicine I, Universitätsklinikum Schleswig-Holstein, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • Boysen TJ; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany.
  • Dalley JW; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany.
  • Lorenz K; Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.
  • Moran C; Department of Psychiatry, University of Cambridge, Cambridge, CB2 2QQ, UK.
  • Rennie KL; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078, Wuerzburg, Germany.
  • Arner A; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Bunsen-Kirchhoff-Str. 11, 44139, Dortmund, Germany.
  • Kirchner H; Wellcome-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
  • Chatterjee K; Beacon Hospital and School of Medicine, University College Dublin, Dublin, Ireland.
  • Mittag J; MRC Epidemiology Unit and Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Nat Commun ; 14(1): 3312, 2023 06 07.
Article em En | MEDLINE | ID: mdl-37286550
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tiroxina / Síndrome da Resistência aos Hormônios Tireóideos Limite: Animals Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tiroxina / Síndrome da Resistência aos Hormônios Tireóideos Limite: Animals Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha