Two common naturally occurring mutations in the human gonadotropin-releasing hormone (GnRH) receptor have differential effects on gonadotropin gene expression and on GnRH-mediated signal transduction

Studies of naturally occurring human GnRH receptor (GnRHR) mutants may provide a useful approach to dissecting the signal transduction pathways involved in mediating the effects of GnRH. We have analyzed two common mutations in the GnRHR, corresponding to amino acid substitutions Gln106Arg and Arg262Gln, for their effects on the stimulation of gonadotropin subunit and GnRHR gene expression by GnRH. Despite similar impairment of GnRH-stimulated inositol phosphate production, dose-response analyses indicated that Gln106Arg and Arg262Gln both reduced the sensitivity of the FSHbeta gene promoter to a greater extent than LHbeta or alphaGSU, suggesting the involvement of more than one signaling pathway. Furthermore, although the sensitivities of the LHbeta and FSHbeta gene promoters to GnRH were similarly affected by both mutants, aGSU sensitivity was decreased to a greater extent by Arg262Gln than by Gln106Arg. Similarly, GnRHR gene promoter sensitivity was significantly reduced only by Arg262Gln. To further characterize the differential downstream effects of these mutant GnRHRs, we investigated their effects on additional signal transduction pathways. The mutant receptors differentially affected GnRH-mediated activation of the ERK pathway and GnRH stimulation of cAMP response element-mediated transcription. These results indicate that measurement of inositol phosphate production alone may not be adequate for assessing mutant GnRHR function and additional signal transduction pathways may better reflect physiologically relevant effects. The differential stimulation of LHbeta, FSHbeta, and alphaGSU gene expression may contribute to the varied phenotypes observed among patients harboring these mutations.