Resistance to thyroid hormone induced tachycardia in RTH syndrome

Mutations in thyroid hormone receptor alpha 1 (TR alpha 1) cause Resistance to Thyroid Hormone alpha (RTH alpha), a disorder characterized by hypothyroidism in TR alpha 1-expressing tissues including the heart. Surprisingly, we report that treatment of RTH alpha patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TR alpha 1 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 TR alpha 1 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 RTH alpha patients with thyroxine in high dosage without concomitant tachycardia, is possible.