Background/Aims: Currently known mutations account for less than 15% of cases with normosmic hypogonadotropic hypogonadism (nIHH). The objective of the study was to identify novel hereditary associations in the pathogenesis of nIHH. Methods: We investigated 26 Turkish patients with nIHH (21 males and 5 females) from 22 families. The coding regions of the GnRH receptor, GnRH1, GPR54, and KISS1 genes were directly sequenced. Results: In two sisters, a novel homozygous missense mutation, R139C, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified. The R139C mutation almost completely abolished plasma membrane expression while having little effect on GnRH-binding affinity. The mutant receptor expression was rescued by a membrane-permeant, non-peptide GnRH receptor antagonist IN3. Conclusions: Consistent with the previous studies we were able to find mutations in only 7.6% of a well-defined group of patients with nIHH, which further suggests that yet unidentified genetic associations to explain nIHH exist.

Keywords:
Hypogonadism, normosmic hypogonadotropic, Gonadotropin-releasing hormone receptor gene, Mutation
1.
Seminara SB, Hayes FJ, Crowley WF: Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 1998;19:521–539.
2.
Karges B, de Roux N: Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocr Dev 2005;8:67–80.
3.
Silveira LF, MacColl GS, Bouloux PM: Hypogonadotropic hypogonadism. Semin Reprod Med 2002;20:327–338.
4.
Achermann JC, Meeks JJ, Jameson JL: Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 2001;185:17–25.
5.
Beranova M, Oliveira LM, Bedecarrats GY, Schipani E, Vallejo M, Ammini AC, Quintos JB, Hall JE, Martin KA, Hayes FJ, Pitteloud N, Kaiser UB, Crowley WF Jr, Seminara SB: Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2001;86:1580–1588.
6.
Bhagavath B, Podolsky RH, Ozata M, Bolu E, Bick DP, Kulharya A, Sherins RJ, Layman LC: Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril 2006;85:706–713.
7.
Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O’Rahilly, S, Aparicio SA: Two Novel Missense Mutations in GPR54 in a Patient with Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab 2005;90:1849–1855.
8.
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–908.
9.
Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O’Rahilly S: Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 2003;112:1550–1560.
10.
Bo-Abbas Y, Acierno JS Jr, Shagoury JK, Crowley WF Jr, Seminara B: Autosomal recessive idiopathic hypogonadotropic hypogonadism: genetic analysis excludes mutations in the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes. J Clin Endocrinol Metab 2003;88:2730–2737.
11.
Seminara SB, Acierno JS Jr, Abdulwahid NA, Crowley WF Jr, Margolin DH: Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J Clin Endocrinol Metab 2002;87:1607–1612.
12.
Lu ZL, Gallagher R, Sellar R, Coetsee M, Millar PR: Mutations remote from the human gonadotropin-releasing hormone (GnRH) receptor binding sites specifically increase binding affinity for GnRH II, but not GnRH I: evidence for ligand-selective receptor active conformations. J Biol Chem 2005;280:29796–29803.
13.
Probst WC, Snyder LA, Schuster DI, Brosius J, Sealfon SC: Sequence alignment of the G-protein coupled receptor superfamily. DNA Cell Biol 1992;11:1–20.
14.
Stojilkovic SS, Reinhar J, Catt KJ: Gonadotropin-releasing hormone receptor: structure and signal transduction pathways. Endocr Rev 1994;15:462–499.
15.
de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E: A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Eng J Med 1997;337:1597–1602.
16.
Layman LC, Cohen DP, Jin M, Xie J, Li Z, Reindollar RH, Bolbolan S, Bick DP, Sherins RR, Duck LW, Musgrove LC, Sellers JC, Neill JD: Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 1998;18:14–15.
17.
Pralong FP, Gomez F, Castillo E, Cotecchia S, Abuin L, Aubert ML, Portman L: Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 1999;84:3811–3816.
18.
Caron P, Chauvin S, Christin-Maitre S, Bennet A, Lahlou N, Counis R, Bouchard P, Kottler M-L: Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metab 1999;84:990–996.
19.
de Roux N, Young J, Brailly-Tabard S, Misrahi M, Milgrom E, Schaison G: The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab 1999;84:567–572.
20.
Kottler M-L, Chauvin S, Lahlou N, Harris CE, Johnson CJ, Lagarde JP, Bouchard P, Farid N, Counis R: A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect. J Clin Endocrinol Metab 2000;85:3002–3008.
21.
Meysing AU, Kanasaki H, Bedecarrats GY, Acierno JS Jr, Conn PM, Martin KA, Seminara SB, Hall JE, Crowley WF Jr, Kaiser UB: GnRH receptor mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. J Clin Endocrinol Metab 2004;89:3189–3198.
22.
Bedecarrats GY, Linher KD, Janovick JA, Beranova M, Kada F, Seminara SB, Michael Conn P, Kaiser UB: Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. Mol Cell Endocrinol 2003;205:51–64.
23.
Costa EM, Bedecarrats GY, Mendonca BB, Arnhold IJ, Kaiser UB, Latronico AC: Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. J Clin Endocrinol Metab 2001;86:2680–2686.
24.
Wolczynski S, Laudanski P, Jarzabek K, Mittre H, Lagarde JP, Kottler ML: A case of complete hypogonadotropic hypogonadism with a mutation in the gonadotropin-releasing hormone receptor gene. Fertil Steril 2003;79:442–444.
25.
Arora KK, Cheng Z, Catt KJ: Mutations of the conserved DRS motif in the second intracellular loop of the gonadotropin-releasing hormone receptor affected expression, activation and internalization. Mol Endocrinol 1997;11:1203–1212.
26.
Ballesteros J, Kitanovic S, Guarnieri F, Davies P, Fromme BJ, Konvicka K, Chi L, Millar RP, Davidson JS, Weinstein H, Sealfon SC: Functional microdomains in G-protein-coupled receptors. The conserved arginine-cage motif in the gonadotropin-releasing hormone receptor. J Biol Chem 1998;273:10445–10453.
27.
Leanos-Miranda A, Janovick JA, Conn PM: Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002;87:4825–4828.
28.
Bernier V, Lagace M, Lonergan M, Arthus MF, Bichet DG, Bouvier M: Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol 2004;18:2074–2084.
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2007
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