Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 4 , Pages 515-528 , December 2006

GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency

  • Nicolas de Roux, MD, PhD (Associate Professor)

      Affiliations

    • Corresponding Author InformationTel.: +33 1 40031985; Fax: +33 1 40409194.

References 

  1. Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocrine Reviews. 2005;26:283–306
  2. Millar RP, Lu ZL, Pawson AJ, et al. Gonadotropin-releasing hormone receptors. Endocrine Reviews. 2004;25:235–275
  3. de Roux N, Young J, Misrahi M, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. The New England Journal of Medicine. 1997;337:1597–1602
  4. Karges B, Karges W, de Roux N. Clinical and molecular genetics of the human GnRH receptor. Human Reproduction Update. 2003;9:523–530
  5. de Roux N, Genin E, Carel J, et al. Hypogonadotropic hypogonadism due to a loss of function of the KiSS-1 derived peptide receptor (GPR54). A new mechanism of regulation of the gonadotropic axis. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:10972–10976
  6. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. The New England Journal of Medicine. 2003;349:1614–1627
  7. Harms JF, Welch DR, Miele ME. KISS1 metastasis suppression and emergent pathways. Clinical & Experimental Metastasis. 2003;20:11–18
  8. Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. The Journal of Clinical Endocrinology and Metabolism. 2005;90:6609–6615
  9. Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145:4073–4077
  10. Matsui H, Takatsu Y, Kumano S, et al. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochemical and Biophysical Research Communications. 2004;320:383–388
  11. Messager S, Chatzidaki EE, Ma D, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:1761–1766
  12. Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology. 2005;146:1689–1697
  13. Thompson EL, Patterson M, Murphy KG, et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. Journal of Neuroendocrinology. 2004;16:850–858
  14. Lee DK, Nguyen T, O'Neill GP, et al. Discovery of a receptor related to the galanin receptors. FEBS Letters. 1999;446:103–107
  15. Kotani M, Detheux M, Vandenbogaerde A, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. The Journal of Biological Chemistry. 2001;276:34631–34636
  16. Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. The Journal of Biological Chemistry. 2001;276:28969–28975
  17. Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613–617
  18. Arora KK, Cheng Z, Catt KJ. Mutations of the conserved DRS motif in the second intracellular loop of the gonadotropin-releasing hormone receptor affect expression, activation, and internalization. Molecular Endocrinology (Baltimore, Md.). 1997;11:1203–1212
  19. Wolczynski S, Laudanski P, Jarzabek K, et al. A case of complete hypogonadotropic hypogonadism with a mutation in the gonadotropin-releasing hormone receptor gene. Fertility and Sterility. 2003;79:442–444
  20. Meysing AU, Kanasaki H, Bedecarrats GY, et al. GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. The Journal of Clinical Endocrinology and Metabolism. 2004;89:3189–3198
  21. Joost P, Methner A. Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands. Genome Biology. 2002;3:0063.1–0063.13
  22. Zajac JM, Mollereau C. RFamide peptides. Introduction. Peptides. 2006;27:941–942
  23. Neill JD, Musgrove LC, Duck LW. Newly recognized GnRH receptors: function and relative role. Trends in Endocrinology and Metabolism. 2004;15:383–392
  24. Pawson AJ, Maudsley S, Morgan K, et al. Inhibition of human type i gonadotropin-releasing hormone receptor (GnRHR) function by expression of a human type II GnRHR gene fragment. Endocrinology. 2005;146:2639–2649
  25. Densmore VS, Urbanski HF. Relative effect of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on gonadotropin release. The Journal of Clinical Endocrinology and Metabolism. 2003;88:2126–2134
  26. Lu ZL, Gallagher R, Sellar R, et al. 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. The Journal of Biological Chemistry. 2005;280:29796–29803
  27. Kauffman AS, Bojkowska K, Wills A, et al. Gonadotropin-releasing hormone-II mRNA and protein content in the mammalian brain are modulated by food intake. Endocrinology. 2006;147:5069–5077
  28. Dobkin-Bekman M, Naidich M, Pawson AJ, et al. Activation of mitogen-activated protein kinase (MAPK) by GnRH is cell-context dependent. Molecular and Cellular Endocrinology. 2006;252:184–190
  29. Bedecarrats GY, Linher KD, Kaiser UB. 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. The Journal of Clinical Endocrinology and Metabolism. 2003;88:834–843
  30. Beranova M, Oliveira LM, Bedecarrats GY, et al. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology and Metabolism. 2001;86:1580–1588
  31. de Roux N, Young J, Brailly-Tabard S, et al. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. The Journal of Clinical Endocrinology and Metabolism. 1999;84:567–572
  32. Dewailly D, Boucher A, Decanter C, et al. Spontaneous pregnancy in a patient who was homozygous for the Q106R mutation in the gonadotropin-releasing hormone receptor gene. Fertility and Sterility. 2002;77:1288–1291
  33. Kottler ML, Chauvin S, Lahlou N, et al. 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. The Journal of Clinical Endocrinology and Metabolism. 2000;85:3002–3008
  34. Layman LC, Cohen DP, Jin M, et al. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nature Genetics. 1998;18:14–15
  35. Leanos-Miranda A, Janovick JA, Conn PM. Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology and Metabolism. 2002;87:4825–4828
  36. Pitteloud N, Boepple PA, DeCruz S, et al. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. The Journal of Clinical Endocrinology and Metabolism. 2001;86:2470–2475
  37. Pralong FP, Gomez F, Castillo E, et al. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. The Journal of Clinical Endocrinology and Metabolism. 1999;84:3811–3816
  38. Seminara SB, Beranova M, Oliveira LM, et al. Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. The Journal of Clinical Endocrinology and Metabolism. 2000;85:556–562
  39. Smith JT, Cunningham MJ, Rissman EF, et al. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146:3686–3692
  40. Smith JT, Dungan HM, Stoll EA, et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology. 2005;146:2976–2984
  41. Funes S, Hedrick JA, Vassileva G, et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochemical and Biophysical Research Communications. 2003;312:1357–1363
  42. Mason AJ, Hayflick JS, Zoeller RT, et al. A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse. Science. 1986;234:1366–1371
  43. Pask AJ, Kanasaki H, Kaiser UB, et al. A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Molecular Endocrinology (Baltimore, Md.). 2005;19:972–981
  44. Mason AJ, Pitts SL, Nikolics K, et al. The hypogonadal mouse: reproductive functions restored by gene therapy. Science. 1986;234:1372–1378
  45. Krieger DT, Perlow MJ, Gibson MJ, et al. Brain grafts reverse hypogonadism of gonadotropin releasing hormone deficiency. Nature. 1982;298:468–471
  46. Cattanach BM, Iddon CA, Charlton HM, et al. Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism. Nature. 1977;269:338–340
  47. Young LS, Speight A, Charlton HM, et al. Pituitary gonadotropin-releasing hormone receptor regulation in the hypogonadotrophic hypogonadal (hpg) mouse. Endocrinology. 1983;113:55–61
  48. McDowell IF, Morris JF, Charlton HM, et al. Effects of luteinizing hormone releasing hormone on the gonadotrophs of hypogonadal (hpg) mice. The Journal of Endocrinology. 1982;95:331–340
  49. Weiss J, Adams E, Whitcomb RW, et al. Normal sequence of the gonadotropin-releasing hormone gene in patients with idiopathic hypogonadotropic hypogonadism. Biology of Reproduction. 1991;45:743–747
  50. Laymann L, Peak D, Jin M. The prevalence and potential effects of gonadotropin releasing hormone gene point mutations in idopathic hypogonadotropic hypogonadism (abstract from an Endocrine Society Meeting). Endocrine Societies. 1996;(P3-40):855
  51. Bhagavath B, Ozata M, Ozdemir IC, et al. The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. Fertility and Sterility. 2005;84:951–957
  52. Janovick JA, Maya-Nunez G, Conn PM. 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. The Journal of Clinical Endocrinology and Metabolism. 2002;87:3255–3262
  53. Janovick JA, Goulet M, Bush E, et al. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. The Journal of Pharmacology and Experimental Therapeutics. 2003;305:608–614
  54. Ulloa-Aguirre A, Janovick JA, Leanos-Miranda A, et al. Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism. Human Reproduction Update. 2004;10:177–192
  55. Brothers SP, Cornea A, Janovick JA, et al. Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. Molecular Endocrinology (Baltimore, Md.). 2004;18:1787–1797
  56. Karges B, de Roux N. Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocrine Development. 2005;8:67–80
  57. Semple RK, Achermann JC, Ellery J, et al. Two novel Missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology and Metabolism. 2005;90:1849–1855
  58. Soderlund D, Canto P, de la Chesnaye E, et al. A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene. Clinical Endocrinology. 2001;54:493–498
  59. Costa EM, Bedecarrats GY, Mendonca BB, et al. Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. The Journal of Clinical Endocrinology and Metabolism. 2001;86:2680–2686
  60. Silveira LF, Stewart PM, Thomas M, et al. Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR ‘knockout’. The Journal of Clinical Endocrinology and Metabolism. 2002;87:2973–2977
  61. Sedlmeyer IL, Pearce CL, Trueman JA, et al. Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing. The Journal of Clinical Endocrinology and Metabolism. 2005;90:1091–1099
  62. Caron P, Chauvin S, Christin-Maitre S, et al. Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. The Journal of Clinical Endocrinology and Metabolism. 1999;84:990–996
  63. Layman LC, Cohen DP, Xie J, et al. Clinical phenotype and infertility treatment in a male with hypogonadotropic hypogonadism due to mutations Ala129Asp/Arg262Gln of the gonadotropin-releasing hormone receptor. Fertility and Sterility. 2002;78:1317–1320
  64. Tsai PS, Moenter SM, Postigo HR, et al. Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Molecular Endocrinology (Baltimore, Md.). 2005;19:225–236
  65. Shahab M, Mastronardi C, Seminara SB, et al. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:2129–2134
  66. Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology. 2005;146:156–163
  67. Seminara SB, Kaiser UB. New Gatekeepers of Reproduction: GPR54 and Its Cognate Ligand, KiSS-1. Endocrinology. 2005;146:1686–1688
  68. Navarro VM, Fernandez-Fernandez R, Castellano JM, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. The Journal of Physiology. 2004;561:379–386
  69. Han SK, Gottsch ML, Lee KJ, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. The Journal of Neuroscience. 2005;25:11349–11356
  70. Lanfranco F, Gromoll J, von Eckardstein S, et al. Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. European Journal of Endocrinology. 2005;153:845–852

PII: S1521-690X(06)00084-4

doi: 10.1016/j.beem.2006.10.005

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 4 , Pages 515-528 , December 2006