Fourteen mutations (13 missense and 1 truncation) of the GnRH receptor (GnRHR) have been identified in patients with hypogonadotropic hypogonadism (HH). We have previously shown that five of the missense mutations can be rescued with a GnRH peptidomimetic antagonist that acts as folding template, stabilizing (otherwise) misfolded GnRHR mutants and thereby restoring function. We now report that this approach rescues 11 of 13 of these GnRHR missense mutants. These data indicate the surprisingly general nature of this approach, an observation that presents therapeutic opportunities for HH and other disorders resulting from protein misfolding. A classification system for GnRHR mutants is proposed.
Preeclampsia is characterized by increased uPRL excretion. uPRL concentrations and their isoforms appear to be suitable markers to assess the severity of preeclampsia and occurrence of adverse outcomes. PRL and and/or its isoforms might be involved in the pathophysiology of preeclampsia.
GnRH plays an essential and central role in neuroendocrine control of reproductive function. The GnRH receptor is located on the plasma membrane of gonadotrophs, pituitary cells that synthesize the gonadotrophins LH and FSH. This receptor belongs to the superfamily of G protein-coupled receptors, and is preferentially coupled to the G(q/11) protein; its activation by GnRH analogues stimulates the synthesis and release of LH and FSH. Resistance to GnRH by inactivating (loss-of-function) mutations of the human GnRH receptor leads to distinct forms of sporadic or inherited hypogonadotrophic hypogonadism. Although in vitro expression of a number of these mutated GnRH receptors in heterologous systems has shown that these mutations appear to alter several functions of the molecule, including ligand binding, receptor activation or interaction with coupled effectors, recent observations from our laboratory have challenged this view and indicated that protein misfolding and resultant misrouting is a mechanism that, by itself, may lead to loss of function of the human GnRH receptor. In this review we describe the experimental data that led us to this conclusion and how these studies revealed previously unsuspected features of the mutant human GnRH receptor.
Loss of function by 11 of 13 naturally occurring mutations in the human GnRH receptor (hGnRHR) was thought to result from impaired ligand binding or effector coupling, but actually results from receptor misrouting. Homo- or heterodimerization of mutant receptors with wild-type (WT) receptors occurs for other G protein-coupled receptors and may result in dominant-negative or -positive effects on the WT receptor. We tested the hypothesis that WT hGnRHR function was affected by misfolded hGnRHR mutants. hGnRHR mutants were found to inhibit the function of WT GnRHR (measured by activation of effector and ligand binding). Inhibition varied depending on the particular hGnRHR mutant coexpressed and the ratio of hGnRHR mutant to WT hGnRHR cDNA cotransfected. The hGnRHR mutants did not interfere with the function of genetically modified hGnRHRs bearing either a deletion of primate-specific Lys(191) or the carboxyl-terminal tail of the catfish GnRHR; these show intrinsically enhanced expression. Moreover, a peptidomimetic antagonist of GnRH enhanced the expression of WT hGnRHR, but not of genetically modified hGnRHR species. The dominant-negative effect of the naturally occurring receptor mutants occurred only for the WT hGnRHR, which has intrinsic low maturation efficiency. The data suggest that this dominant negative effect accompanies the diminished plasma membrane expression as a recent evolutionary event.
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