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Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor¹

Division of Endocrinology, Department of Medicine (F.P.P, F.G., E.C., L.P., R.C.G.), Institute of Pharmacology (S.C., L.A.), University Hospital, 1011 Lausanne; and the Division of Biology of Growth and Reproduction, University Hospital (M.L.A.), 1211 Geneva 14, Switzerland

Address all correspondence and requests for reprints to: François P. Pralong, M.D., Division of Endocrinology, BH 19–707, CHUV, 1011 Lausanne, Switzerland. E-mail: francois.pralong{at}chuv.hospvd.ch

In this study, we describe a patient with a phenotype of complete hypogonadotropic hypogonadism who presented primary failure of pulsatile GnRH therapy, but responded to exogenous gonadotropin administration. This patient bore a novel point mutation (T for A) at codon 168 of the gene encoding the GnRH receptor (GnRH-R), resulting in a serine to arginine change in the fourth transmembrane domain of the receptor. This novel mutation was present in the homozygous state in the patient, whereas it was in the heterozygous state in both phenotypically normal parents. When introduced into the complementary DNA coding for the GnRH-R, this mutation resulted in the complete loss of the receptor-mediated signaling response to GnRH.

In conclusion, we report the first mutation of the GnRH-R gene that can induce a total loss of function of this receptor and is associated with a phenotype of complete hypogonadotropic hypogonadism.

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