Altered cardiac phenotype in transgenic mice carrying the Δ337 threonine thyroid hormone receptor β mutant derived from the S family

The heart has been recognized as a major target of thyroid hormone action. Our study investigates both the regulation of cardiac-specific genes and contractile behavior of the heart in the presence of a mutant thyroid hormone receptor β1 (T₃Rβ1-Δ337T) derived from the S kindred. The mutant receptor was originally identified in a patient with generalized resistance to thyroid hormone. Cardiac expression of the mutant receptor was achieved by a transgenic approach in mice. As the genes for myosin heavy chains (MHCα and MHCβ) and the cardiac sarcoplasmic reticulum Ca²⁺ adenosine triphosphatase (SERCA2) are known to be regulated by T₃, their cardiac expression was analyzed. The messenger RNA levels for MHCα and SERCA2 were markedly down-regulated, MHCβ messenger RNA was up-regulated. Although T₃ levels were normal in these animals, this pattern of cardiac gene expression mimics a hypothyroid phenotype. Cardiac muscle contraction was significantly prolonged in papillary muscles from transgenic mice. The electrocardiogram of transgenic mice showed a substantial prolongation of the QRS interval. Changes in cardiac gene expression, cardiac muscle contractility, and electrocardiogram are compatible with a hypothyroid cardiac phenotype despite normal T₃ levels, indicating a dominant negative effect of the T₃Rβ mutant.