The lutropin/choriogonadotropin receptor (LHR), a member of the G protein-coupled receptor family, plays a key role in reproductive human physiology. Dominant missense mutations that produce agonist- independent LHR activation of the cyclic AMP pathway have been shown to cause male-limited precocious puberty with Leydig cell hyperplasia, while inactivating mutations of the LHR gene are the basis of autosomal recessive Leydig cell hypoplasia. Preliminary data presented in this proposal reveal that Leydig cell neoplasia is also associated with an LHR mutation, in this case a novel somatic mutation that encodes D578H. This mutation not only causes strong constitutive activation of the cyclic AMP pathway, but also causes activation of the phospholipase C and c-Jun kinase cascades. Very little is known about the spectrum of G proteins normally activated by the LHR and about the specific pathways involved in mitogenesis of Leydig cells. The discovery of different activating mutations of the human LHR that are associated with either hyperplasia or neoplasia provides an excellent opportunity to define the role that cAMP and other G protein-mediated signaling cascades play in effects mediated by normal and mutant forms of the LHR.
The specific aims of this proposal are: 1) To determine whether novel activating mutations of the LHR gene are a common cause of human Leydig cell neoplasia, 2) To define the G protein coupling and downstream signaling properties of the adenoma-associated D578H mutation which distinguish it from activating receptor mutations associated with hyperplasia, and 3) To compare the mitogenic effects of D578H with those of other activated LHR mutants in a model fibroblast system and in purified mouse Leydig cells.
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