Altered cardiac phenotype in transgenic mice carrying the Delta 337 threonine thyroid hormone receptor beta 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 co ntractile behavior of the heart in the presence of a mutant thyroid hormone receptor beta 1 (T3R beta 1-Delta 337T) derived from the S kindred. The mu tant receptor was originally identified in a patient with generalized resis tance to thyroid hormone. Cardiac expression of the mutant receptor was ach ieved by a transgenic approach in mice. As the genes for myosin heavy chain s (MHC alpha and MHC beta) and the cardiac sarcoplasmic reticulum Ca2+ aden osine triphosphatase (SERCA2) are known to be regulated by T-3, their cardi ac expression was analyzed. The messenger RNA levels for MHC alpha and SERC A2 were markedly down-regulated, MHC beta messenger RNA was up-regulated. A lthough T-3 levels were normal in these animals, this pattern of cardiac ge ne expression mimics a hypothyroid phenotype. Cardiac muscle contraction wa s significantly prolonged in papillary muscles from transgenic mice. The el ectrocardiogram of transgenic mice showed a substantial prolongation of the QRS interval. Changes in cardiac gene expression, cardiac muscle contracti lity, and electrocardiogram are compatible with a hypothyroid cardiac pheno type despite normal T-3 levels, indicating a dominant negative effect of th e T3R beta mutant.