In addition to entrapment of wild-type TSHR in endoplasmic reticulum by the mutant receptor, which induces TSH resistance in humans [17], this is the first report linking dominant negative mutations of a G protein-coupled receptor integrating in plasma membrane to an abnormal endocrine phenotype in mammals, and provides an explanation for hypothyroidism in C.RF-Tshrhyt/wild mice. This evidence concerns the gene TSHR and hypothyroidism.