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Submitted on October 2, 2006
Accepted on December 5, 2006
Pediatric Endocrine Unit, Ha'Emek Medical Center, Afula, Israel; Technion Faculty of Medicine, Haifa, Israel; Maternité Pellegrin, CHU Bordeaux, 33076 Bordeaux, France; INSERM U690, Paris, Hôpital Robert Debré. 75019 Paris, France; Université Paris 11, Faculté de Médecine Paris Sud, 94275 Le Kremlin Bicêtre, France
* To whom correspondence should be addressed. E-mail: deroux{at}rdebre.inserm.fr.
Context: Loss of function of the G-protein-coupled receptor of kisspeptins (GPR54) was recently described as a new cause of isolated hypogonadotropic hypogonadism (IHH). In-vivo studies performed in several species have confirmed the major role of kisspeptins in neuroendocrine regulation of the gonadotropic axis and therefore sexual maturation.
Objective: To specify the exact contribution of kisspeptins and GPR54 to the initiation of puberty in humans.
Design: Detailed neuroendocrine descriptions were performed in five IHH patients bearing a new GPR54-inactivating mutation.
Results: A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in the five affected patients. This substitution completely inhibited GPR54 signaling. Phenotypic analysis revealed variable expressivity in the same family--either partial or complete gonadotropic deficiency. LH pulsatility analysis showed peaks with normal frequency but low amplitude. Repeated GnRH tests performed between 12 and 21 y of age in one affected male revealed progressive changes in pituitary response from an early pubertal to an almost full pubertal pattern. Double GnRH test stimulations performed at a 120-min interval showed reduce dynamic pituitary response in GPR54-mutated patients.
Conclusion: GPR54 inactivation does not impede neuroedocrine onset of puberty; rather, it delays and slows down pubertal maturation of the gonadotropic axis. The L102P loss of function mutation in GPR54 results in a more quantitative than qualitative defect of gonadotropic axis activation.
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