Legend to figure 5: Structural model of the TSHR with indication of loss-of-function mutations. The location and substitutions responsible for known loss-of-function mutations (side-chains as blue sticks) are indicated on a three-dimensional receptor model. Single letter abbreviations of amino-acids are used. In contrast to activating mutations, many inactivating mutations are located also in the LRRD. As observable in this complex model inactivating mutations can have different molecular effects on TSHR functions dependent on their localization, like diminishing hormone binding (location in the LRRD, e.g. R109Q), G-protein binding (intracellular localization, e.g. M527T, R531W), leading to a decreased receptor cell surface expression by modification of the three-dimensional structure (e.g. mutations at extracellular cysteines which interrupts stabilizing disulfide bridges, e.g. C390W), or interrupting the signal transport in the serpentine domain (located at the helices, e.g. A593V).