Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism.

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.