Institute for Endocrinology and Diabetes, Center of Brain Behavior & Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
National Institute Health and Care Research Cambridge Clinical Research Facility, Addenbrooke's Hospital, Cambridge, UK.
Nat Commun. 2023 Jun 7;14(1):3312. doi: 10.1038/s41467-023-38960-1.
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.
甲状腺激素受体 α1 (TRα1) 的突变导致甲状腺激素抵抗 α (RTHα)，这是一种以 TRα1 表达组织（包括心脏）发生甲状腺功能减退为特征的疾病。令人惊讶的是，我们报告称，用甲状腺素治疗 RTHα 患者以克服组织激素抵抗并不会提高他们的心率。TRα1 突变雄性小鼠的心脏遥测表明，这种持续心动过缓是由内在的心脏缺陷引起的，而不是由于自主神经控制的改变。转录组分析显示，起搏器通道 (Hcn2、Hcn4) 的甲状腺激素 (T3) 依赖性上调保持不变，但控制心率的几个离子通道基因的表达却不可逆转地减少。在子宫内暴露于较高母体 T3 浓度的 TRα1 突变雄性小鼠中，可恢复离子通道（包括 Ryr2）的改变表达和 DNA 甲基化。我们的研究结果表明，除了 Hcn2 和 Hcn4 之外，其他靶基因介导 T3 诱导的心动过速，并表明 RTHα 患者用甲状腺素进行高剂量治疗而不伴随心动过速是可能的。
