Nature communications · 2023
Resistance to thyroid hormone induced tachycardia in RTHα syndrome.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.