Effects Of Luteinizing Hormone Receptor

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Constitutive activating mutations of the human Luteinizing hormone/chorionic gonadotropin hormone receptor (LHR) causes familial male-limited precocious puberty (FMPP). In collaboration with Dr. Malcolm Martin, Georgetown University, and Dr. Ellen Leschek, Developmental Endocrinology Branch, we have identified two FMPP patients who developed testicular neoplasia. To study the impact of constitutive activation of the LH/hCG signaling pathway on spermatogenesis and sexual development, and the potential tumorigenic effect of a constitutively activated LHR, we have generated an in vitro cell model and are in the process of generating a transgenic animal model. MA-10 cells were transfected with activating LHR mutations. The profile of expressed genes in cells expressing the mutated LHR was compared with that of control cells. Preliminary studies of one mutated LHR indicated up-regulation of genes associated with cell proliferation and down-regulation of genes associated with differentiation. Interestingly, several genes known to be involved in spermatogenesis were also down-regulated in cells expressing the mutated LHR. This study is being repeated with different mutated LHR genes with analysis employing a more extensive mouse cDNA microarray. We are generating constructs of LHR carrying activating mutations for introduction into mouse ES cells to generate a transgenic animal model of FMPP for the study of the impact of constitutively activated LHR gene on spermatogenesis and sexual development.