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Previous Volume 337:1597-1603 November 27, 1997 Number 22 Next

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Hypogonadotropic hypogonadism is often associated with anosmia in a condition known as Kallmann's syndrome. The gene for the X-linked form of Kallmann's syndrome has been mapped to chromosome Xp22.3,¹ and several mutations have been described.^2,3,4 In idiopathic hypogonadotropic hypogonadism there is no anosmia, and the involved genes have not been characterized. One possible candidate is the gene for gonadotropin-releasing hormone (GnRH), especially since hypogonadal mice with the deletion of this gene have been identified.⁵ However, no abnormality of the gene for GnRH has been found in several patients with idiopathic hypogonadotropic hypogonadism.^6,7,8,9 The gene for the GnRH receptor is another . . . [Full Text of this Article]

Case Reports

Methods

Luteinizing Hormone

DNA Sequencing

Transfection and Functional Studies

Results

Sequencing of the Gnrh-Receptor Gene

Hormone Binding by Mutant Receptors

Hormone-Induced Activation of Phospholipase C by Mutant Receptors

Discussion

Source Information

From Inserm Unité 135, Institut Fédératif de Recherche 21 (Hormones et Génétique) (N.R., M.M., E.M.), and the Service d'Endocrinologie et des Maladies de la Reproduction, Institut Fédératif de Recherche 21 (Hormones et Génétique) (J.Y., P.C., G.S.), Hôpital de Bicêtre, Le Kremlin-Bicêtre; and Commissariat d'Énergie Atomique/Saclay, Département d'Ingénierie et d'Étude des Protéines, Gif-sur-Yvette (R.G.) — both in France.

Address reprint requests to Dr. Schaison at the Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France.

References

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• Guran, T., Tolhurst, G., Bereket, A., Rocha, N., Porter, K., Turan, S., Gribble, F. M., Kotan, L. D., Akcay, T., Atay, Z., Canan, H., Serin, A., O'Rahilly, S., Reimann, F., Semple, R. K., Topaloglu, A. K. (2009). Hypogonadotropic Hypogonadism due to a Novel Missense Mutation in the First Extracellular Loop of the Neurokinin B Receptor. J. Clin. Endocrinol. Metab. 94: 3633-3639 [Abstract] [Full Text]  
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• Wehkalampi, K., Widen, E., Laine, T., Palotie, A., Dunkel, L. (2008). Association of the Timing of Puberty with a Chromosome 2 Locus. J. Clin. Endocrinol. Metab. 93: 4833-4839 [Abstract] [Full Text]  
• Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., VanVliet, G., Pearce, S., Crowley, W. F. Jr., Zhou, Q.-Y., Pitteloud, N. (2008). Mutations in Prokineticin 2 and Prokineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum. J. Clin. Endocrinol. Metab. 93: 3551-3559 [Abstract] [Full Text]  
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• Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., Crowley, W. F. Jr. (2007). From the Cover: Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc. Natl. Acad. Sci. USA 104: 17447-17452 [Abstract] [Full Text]  
• Conn, P. M., Ulloa-Aguirre, A., Ito, J., Janovick, J. A. (2007). G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo. Pharmacol. Rev. 59: 225-250 [Abstract] [Full Text]  
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• Lanfranco, F., Gromoll, J., von Eckardstein, S., Herding, E. M, Nieschlag, E., Simoni, M. (2005). Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 153: 845-852 [Abstract] [Full Text]  
• Trarbach, E. B, Baptista, M. T M, Garmes, H. M, Hackel, C. (2005). Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients. J Endocrinol 187: 361-368 [Abstract] [Full Text]  
• Seminara, S. B. (2005). We All Remember Our First Kiss: Kisspeptin and the Male Gonadal Axis. J. Clin. Endocrinol. Metab. 90: 6738-6740 [Full Text]  
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• Grumbach, M. M. (2005). A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant. J. Clin. Endocrinol. Metab. 90: 3122-3127 [Abstract] [Full Text]  
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• Brothers, S. P., Cornea, A., Janovick, J. A., Conn, P. M. (2004). Human Loss-of-Function Gonadotropin-Releasing Hormone Receptor Mutants Retain Wild-Type Receptors in the Endoplasmic Reticulum: Molecular Basis of the Dominant-Negative Effect. Mol. Endocrinol. 18: 1787-1797 [Abstract] [Full Text]  
• Millar, R. P., Lu, Z.-L., Pawson, A. J., Flanagan, C. A., Morgan, K., Maudsley, S. R. (2004). Gonadotropin-Releasing Hormone Receptors. Endocr. Rev. 25: 235-275 [Abstract] [Full Text]  
• Ulloa-Aguirre, A., Janovick, J. A., Leanos-Miranda, A., Conn, P. M. (2004). Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism. Hum Reprod Update 10: 177-192 [Abstract] [Full Text]  
• Brothers, S. P., Janovick, J. A., Conn, P. M. (2003). Unexpected Effects of Epitope and Chimeric Tags on Gonadotropin-Releasing Hormone Receptors: Implications for Understanding the Molecular Etiology of Hypogonadotropic Hypogonadism. J. Clin. Endocrinol. Metab. 88: 6107-6112 [Abstract] [Full Text]  
• de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., Milgrom, E. (2003). Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl. Acad. Sci. USA 100: 10972-10976 [Abstract] [Full Text]  
• Bo-Abbas, Y., Acierno, J. S. Jr., Shagoury, J. K., Crowley, W. F. Jr., Seminara, S. B. (2003). Autosomal Recessive Idiopathic Hypogonadotropic Hypogonadism: Genetic Analysis Excludes Mutations in the Gonadotropin-Releasing Hormone (GnRH) and GnRH Receptor Genes. J. Clin. Endocrinol. Metab. 88: 2730-2737 [Abstract] [Full Text]  
• Karges, B., Karges, W., Mine, M., Ludwig, L., Kuhne, R., Milgrom, E., de Roux, N. (2003). Mutation Ala171Thr Stabilizes the Gonadotropin-Releasing Hormone Receptor in Its Inactive Conformation, Causing Familial Hypogonadotropic Hypogonadism. J. Clin. Endocrinol. Metab. 88: 1873-1879 [Abstract] [Full Text]  
• Bedecarrats, G. Y., Linher, K. D., Kaiser, U. B. (2003). 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. J. Clin. Endocrinol. Metab. 88: 834-843 [Abstract] [Full Text]  
• Conn, P. M., Leanos-Miranda, A., Janovick, J. A. (2002). Protein Origami: Therapeutic Rescue of Misfolded Gene Products. Mol. Interv. 2: 308-316 [Abstract] [Full Text]  
• Janovick, J. A., Maya-Nunez, G., Conn, P. M. (2002). Rescue of Hypogonadotropic Hypogonadism-Causing and Manufactured GnRH Receptor Mutants by a Specific Protein-Folding Template: Misrouted Proteins as a Novel Disease Etiology and Therapeutic Target. J. Clin. Endocrinol. Metab. 87: 3255-3262 [Abstract] [Full Text]  
• Achermann, J. C., Ozisik, G., Meeks, J. J., Jameson, J. L. (2002). Genetic Causes of Human Reproductive Disease. J. Clin. Endocrinol. Metab. 87: 2447-2454 [Full Text]  
• Kalantaridou, S. N., Chrousos, G. P. (2002). Monogenic Disorders of Puberty. J. Clin. Endocrinol. Metab. 87: 2481-2494 [Full Text]  
• Maya-Nunez, G., Janovick, J. A., Ulloa-Aguirre, A., Soderlund, D., Conn, P. M., Mendez, J. P. (2002). Molecular Basis of Hypogonadotropic Hypogonadism: Restoration of Mutant (E90K) GnRH Receptor Function by a Deletion at a Distant Site. J. Clin. Endocrinol. Metab. 87: 2144-2149 [Abstract] [Full Text]  
• Layman, L C (2002). Human gene mutations causing infertility. J. Med. Genet. 39: 153-161 [Abstract] [Full Text]  
• Pitteloud, N., Hayes, F. J., Boepple, P. A., DeCruz, S., Seminara, S. B., MacLaughlin, D. T., Crowley, W. F. Jr. (2002). The Role of Prior Pubertal Development, Biochemical Markers of Testicular Maturation, and Genetics in Elucidating the Phenotypic Heterogeneity of Idiopathic Hypogonadotropic Hypogonadism. J. Clin. Endocrinol. Metab. 87: 152-160 [Abstract] [Full Text]  
• Pitteloud, N., Boepple, P. A., DeCruz, S., Valkenburgh, S. B., Crowley, W. F. Jr., Hayes, F. J. (2001). The Fertile Eunuch Variant of Idiopathic Hypogonadotropic Hypogonadism: Spontaneous Reversal Associated with a Homozygous Mutation in the Gonadotropin-Releasing Hormone Receptor. J. Clin. Endocrinol. Metab. 86: 2470-2475 [Abstract] [Full Text]  
• Costa, E. M. F., Bedecarrats, G. Y., Mendonca, B. B., Arnhold, I. J. P., Kaiser, U. B., Latronico, A. C. (2001). Two Novel Mutations in the Gonadotropin-Releasing Hormone Receptor Gene in Brazilian Patients with Hypogonadotropic Hypogonadism and Normal Olfaction. J. Clin. Endocrinol. Metab. 86: 2680-2686 [Abstract] [Full Text]  
• Beranova, M., Oliveira, L. M. B., BÉdÉcarrats, G. Y., Schipani, E., Vallejo, M., Ammini, A. C., Quintos, J. B., Hall, J. E., Martin, K. A., Hayes, F. J., Pitteloud, N., Kaiser, U. B., Crowley, W. F. Jr., Seminara, S. B. (2001). Prevalence, Phenotypic Spectrum, and Modes of Inheritance of Gonadotropin-Releasing Hormone Receptor Mutations in Idiopathic Hypogonadotropic Hypogonadism. J. Clin. Endocrinol. Metab. 86: 1580-1588 [Abstract] [Full Text]  
• Seminara, S. B., Beranova, M., Oliveira, L. M. B., Martin, K. A., Crowley, W. F. Jr., Hall, J. E. (2000). Successful Use of Pulsatile Gonadotropin-Releasing Hormone (GnRH) for Ovulation Induction and Pregnancy in a Patient with GnRH Receptor Mutations. J. Clin. Endocrinol. Metab. 85: 556-562 [Abstract] [Full Text]  
• (1999). Mutational Analysis of DAX1 in Patients with Hypogonadotropic Hypogonadism or Pubertal Delay. J. Clin. Endocrinol. Metab. 84: 4497-4500 [Abstract] [Full Text]  
• (1999). Expression of Prolactin-Releasing Peptide and Its Receptor Messenger Ribonucleic Acid in Normal Human Pituitary and Pituitary Adenomas. J. Clin. Endocrinol. Metab. 84: 4652-4655 [Abstract] [Full Text]  
• Pralong, F. P., Gomez, F., Castillo, E., Cotecchia, S., Abuin, L., Aubert, M. L., Portmann, L., Gaillard, R. C. (1999). Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor. J. Clin. Endocrinol. Metab. 84: 3811-3816 [Abstract] [Full Text]  
• Norwitz, E. R., Jeong, K.-H., Chin, W. W. (1999). Molecular Mechanisms of Gonadotropin-Releasing Hormone Receptor Gene Regulation. Reproductive Sciences 6: 169-178 [Abstract]  
• Achermann, J. C., Jameson, J. L. (1999). Fertility and Infertility: Genetic Contributions from the Hypothalamic-Pituitary- Gonadal Axis. Mol. Endocrinol. 13: 812-818 [Full Text]  
• Adashi, E. Y., Hennebold, J. D. (1999). Single-Gene Mutations Resulting in Reproductive Dysfunction in Women. NEJM 340: 709-718 [Full Text]  
• Caron, P., Chauvin, S., Christin-Maitre, S., Bennet, A., Lahlou, N., Counis, R., Bouchard, P., Kottler, M.-L. (1999). Resistance of Hypogonadic Patients with Mutated GnRH Receptor Genes to Pulsatile GnRH Administration. J. Clin. Endocrinol. Metab. 84: 990-996 [Abstract] [Full Text]  
• de Roux, N., Young, J., Brailly-Tabard, S., Misrahi, M., Milgrom, E., Schaison, G. (1999). The Same Molecular Defects of the Gonadotropin-Releasing Hormone Receptor Determine a Variable Degree of Hypogonadism in Affected Kindred. J. Clin. Endocrinol. Metab. 84: 567-572 [Abstract] [Full Text]  
• Seminara, S. B., Hayes, F. J., Crowley, W. F. Jr. (1998). Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann's Syndrome): Pathophysiological and Genetic Considerations. Endocr. Rev. 19: 521-539 [Abstract] [Full Text]