Activating mutations of the lutropin choriogonadotropin receptor in precocious puberty.

The human receptor for lutropin and chorionic gonadotropin (LHR) is a member of the G-protein-coupled receptor superfamily and plays a key role in normal and abnormal reproductive physiology. Naturally occurring mutations of the LHR gene that lead to hormone-independent signaling are associated with abnormal Leydig cell growth and precocious puberty in boys. These mutations affect 13 different residues in the LHR, with the majority clustered in the cytoplasmic half of transmembrane helix 6. Germline LHR mutations that produce constitutive activation of the Gs pathway are found in cases of Leydig cell hyperplasia, while a unique somatic LHR mutation capable of activating both the Gs and Gq signaling pathways has been identified in Leydig cell tumors. The newly determined crystal structure of bovine rhodopsin provides a useful framework for interpreting the effects of these disease-associated LHR mutations in the context of conserved structural motifs in helix 3 and helix 7 that are known to be involved in receptor activation. As with rhodopsin, conformational signaling appears to depend on the rearrangement of key electrostatic, hydrogen-bond, and hydrophobic interactions that normally serve to stabilize the inactive LHR conformation.