Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations

  • Suzy Drummond Carvalho Bianco
  • Ursula B. Kaiser
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 784)


Kisspeptin receptor (KISS1R) signaling is essential for the hallmark increase in pulsatile GnRH secretion characteristic of the onset of puberty in humans and experimental animals. Loss-of-function mutations in KISS1R are associated with idiopathic hypogonadotropic hypogonadism in humans. Also, mutations with confirmed association with idiopathic central precocious puberty were identified in kisspeptin and KISS1R. These observations underscore the role of KISS1R signaling for normal pubertal development. Moreover, investigation of the mechanisms underlying the gain-of-function mutation in KISS1R indicates that the duration of KISS1R signaling is critical for the role of this receptor in timing the onset of puberty in humans. These findings further endorse the need to uncover the mechanisms, as well as yet-unknown proteins, involved in each step of KISS1R signaling. This knowledge is expected to advance our understanding of normal and abnormal pubertal development, as well as to help uncover the role of KISS1R signaling in non-hypothalamic tissues such as the placenta. This chapter discusses recent advances in the investigation of KISS1R signaling and function, as well as potential pathophysiological implications of naturally occurring mutations in this receptor identified in humans with reproductive disorders.



This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), through cooperative agreement U54 HD28138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research, by R01 HD61577, and by R21 HD66495 (to UBK) as well as by the R21 HD059015 and ARRA R21 HD059015-02S1 (SDCB) and by the 2008 Child Health Research Award from the Charles H. Hood Foundation, Boston, MA (SDCB).


  1. 1.
    Plant TM (2002) Neurophysiology of puberty. J Adolesc Health 31:185–191PubMedCrossRefGoogle Scholar
  2. 2.
    Seminara SB, Hayes FJ, Crowley WF Jr (1998) Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 19:521–539PubMedCrossRefGoogle Scholar
  3. 3.
    Cadman SM, Kim SH, Hu Y, Gonzalez-Martinez D, Bouloux PM (2007) Molecular pathogenesis of Kallmann’s syndrome. Horm Res 67:231–242PubMedCrossRefGoogle Scholar
  4. 4.
    Chan YM, Broder-Fingert S, Seminara SB (2009) Reproductive functions of kisspeptin and Gpr54 across the life cycle of mice and men. Peptides 30:42–48PubMedCrossRefGoogle Scholar
  5. 5.
    Iovane A, Aumas C, de Roux N (2004) New insights in the genetics of isolated hypogonadotropic hypogonadism. Eur J Endocrinol 151(Suppl 3):U83–88PubMedCrossRefGoogle Scholar
  6. 6.
    Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC (2008) A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 358:709–715PubMedCrossRefGoogle Scholar
  7. 7.
    Trarbach EB, Silveira LG, Latronico AC (2007) Genetic insights into human isolated gonadotropin deficiency. Pituitary 10:381–391PubMedCrossRefGoogle Scholar
  8. 8.
    de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 100:10972–10976PubMedCrossRefGoogle Scholar
  9. 9.
    Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1627PubMedCrossRefGoogle Scholar
  10. 10.
    Lanfranco F, Gromoll J, von Eckardstein S, Herding EM, 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 153:845–852PubMedCrossRefGoogle Scholar
  11. 11.
    Nimri R, Lebenthal Y, Lazar L, Chevrier L, Phillip M, Bar M, Hernandez-Mora E, de Roux N, Gat-Yablonski G (2011) A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab 96:E536–545PubMedCrossRefGoogle Scholar
  12. 12.
    Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF Jr, Seminara SB (2006) Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Mol Cell Endocrinol 254–255:70–77PubMedCrossRefGoogle Scholar
  13. 13.
    Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O’Rahilly S, Aparicio SA (2005) Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 90:1849–1855PubMedCrossRefGoogle Scholar
  14. 14.
    Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N (2007) Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 92:1137–1144PubMedCrossRefGoogle Scholar
  15. 15.
    Teles MG, Trarbach EB, Noel SD, Guerra-Junior G, Jorge A, Beneduzzi D, Bianco SD, Mukherjee A, Baptista MT, Costa EM, De Castro M, Mendonca BB, Kaiser UB, Latronico AC (2010) A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism. Eur J Endocrinol 163:29–34PubMedCrossRefGoogle Scholar
  16. 16.
    Chan YM, Broder-Fingert S, Paraschos S, Lapatto R, Au M, Hughes V, Bianco SD, Min L, Plummer L, Cerrato F, De Guillebon A, Wu IH, Wahab F, Dwyer A, Kirsch S, Quinton R, Cheetham T, Ozata M, Ten S, Chanoine JP, Pitteloud N, Martin KA, Schiffmann R, Van der Kamp HJ, Nader S, Hall JE, Kaiser UB, Seminara SB (2011) GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1. J Clin Endocrinol Metab 96:E1771–1781PubMedCrossRefGoogle Scholar
  17. 17.
    Silveria LGNS, Silveira-Neto AP, Abreu AP, Brito VN, Santos MGBS, Kuohung W, Xu S, Gryngarten M, Escobar MEAI, Mendonca BB, Kaiser UB, Latronico AC (2010) Mutations of the KISS1 Gene in Disorders of Puberty. J Clin Endocrinol Metab 95:2276–2280CrossRefGoogle Scholar
  18. 18.
    Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B (2012) Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 366:629–635PubMedCrossRefGoogle Scholar
  19. 19.
    Breuer O, Abdulhadi-Atwan M, Zeligson S, Fridman H, Renbaum P, Levy-Lahad E, Zangen DH (2012) A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia. Eur J Endocrinol 167(2):209–16PubMedGoogle Scholar
  20. 20.
    d’Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, Aparicio SA, Colledge WH (2007) Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA 104:10714–10719PubMedCrossRefGoogle Scholar
  21. 21.
    Dungan HM, Gottsch ML, Zeng H, Gragerov A, Bergmann JE, Vassilatis DK, Clifton DK, Steiner RA (2007) The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone. J Neurosci 27:12088–12095PubMedCrossRefGoogle Scholar
  22. 22.
    Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL (2003) The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 312:1357–1363PubMedCrossRefGoogle Scholar
  23. 23.
    Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB (2007) Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 148:4927–4936PubMedCrossRefGoogle Scholar
  24. 24.
    Mei H, Walters C, Carter R, Colledge WH (2011) Gpr54-/- mice show more pronounced defects in spermatogenesis than Kiss1-/- mice and improved spermatogenesis with age when exposed to dietary phytoestrogens. Reproduction 141:357–366PubMedCrossRefGoogle Scholar
  25. 25.
    Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M, Escobar ME, Arnhold IJ, Mendonca BB, Kaiser UB, Latronico AC (2010) Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 95:2276–2280PubMedCrossRefGoogle Scholar
  26. 26.
    Luan X, Yu H, Wei X, Zhou Y, Wang W, Li P, Gan X, Wei D, Xiao J (2007) GPR54 polymorphisms in Chinese girls with central precocious puberty. Neuroendocrinology 86:77–83PubMedCrossRefGoogle Scholar
  27. 27.
    Luan X, Zhou Y, Wang W, Yu H, Li P, Gan X, Wei D, Xiao J (2007) Association study of the polymorphisms in the KISS1 gene with central precocious puberty in Chinese girls. Eur J Endocrinol 157:113–118PubMedCrossRefGoogle Scholar
  28. 28.
    Parhar IS, Ogawa S, Sakuma Y (2004) Laser-captured single digoxigenin-labeled neurons of gonadotropin-releasing hormone types reveal a novel G protein-coupled receptor (Gpr54) during maturation in cichlid fish. Endocrinology 145:3613–3618PubMedCrossRefGoogle Scholar
  29. 29.
    Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA (2004) Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80:264–272PubMedCrossRefGoogle Scholar
  30. 30.
    Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA (2005) Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 102:1761–1766PubMedCrossRefGoogle Scholar
  31. 31.
    Shibata M GR, Shahab M, Plant TM (2005) GnRH neurons in the peripubertal male rhesus monkey (Macaca mulatta) express GPR54: implication for the control of primate puberty. In: 87th Annual Meeting of the Endocrine Society. San Diego, CAGoogle Scholar
  32. 32.
    Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE (2005) Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25:11349–11356PubMedCrossRefGoogle Scholar
  33. 33.
    Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E (2008) An increase in kisspeptin-54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-1 release in the stalk-median eminence of female rhesus monkeys in vivo. Endocrinology 149:4151–4157PubMedCrossRefGoogle Scholar
  34. 34.
    Herbison AE, de Tassigny X, Doran J, Colledge WH (2010) Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151:312–321PubMedCrossRefGoogle Scholar
  35. 35.
    Kurian JR, Keen KL, Guerriero KA, Terasawa E (2012) Tonic control of kisspeptin release in prepubertal monkeys: implications to the mechanism of puberty onset. Endocrinology 153:3331–3336PubMedCrossRefGoogle Scholar
  36. 36.
    Kauffman AS, Park JH, McPhie-Lalmansingh AA, Gottsch ML, Bodo C, Hohmann JG, Pavlova MN, Rohde AD, Clifton DK, Steiner RA, Rissman EF (2007) The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J Neurosci 27:8826–8835PubMedCrossRefGoogle Scholar
  37. 37.
    Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M (2001) The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 276:34631–34636PubMedCrossRefGoogle Scholar
  38. 38.
    Oishi SMR, Tomita K, Setsuda S, Masuda R, Ohno H, Naniwa Y, Ieda N, Inoue N, Ohkura S, Uenoyama Y, Tsukamura H, Maeda K, Hirasawa A, Tsujimoto G, Fijii N (2011) Activation of neuropeptide FF receptors by kisspeptin receptor ligands. ACS Med Chem Lett 2:5CrossRefGoogle Scholar
  39. 39.
    Colledge WH, d’Anglemont de Tassigny X (2010) The role of kisspeptin signalling in the regulation of the GnRH-gonadotrophin ovarian axis in mice. Ann Endocrinol (Paris) 71:198–200CrossRefGoogle Scholar
  40. 40.
    Pampillo M, Camuso N, Taylor JE, Szereszewski JM, Ahow MR, Zajac M, Millar RP, Bhattacharya M, Babwah AV (2009) Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. Mol Endocrinol 23:2060–2074PubMedCrossRefGoogle Scholar
  41. 41.
    Bianco SD, Vandepas L, Correa-Medina M, Gereben B, Mukherjee A, Kuohung W, Carroll R, Teles MG, Latronico AC, Kaiser UB (2011) KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology 152:1616–1626PubMedCrossRefGoogle Scholar
  42. 42.
    Lee DK, Nguyen T, O’Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-­Nguyen AT, George SR, O’Dowd BF (1999) Discovery of a receptor related to the galanin receptors. FEBS Lett 446:103–107PubMedCrossRefGoogle Scholar
  43. 43.
    Gottsch ML, Clifton DK, Steiner RA (2009) From KISS1 to kisspeptins: An historical perspective and suggested nomenclature. Peptides 30:4–9PubMedCrossRefGoogle Scholar
  44. 44.
    Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M (2001) Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411:613–617PubMedCrossRefGoogle Scholar
  45. 45.
    Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC (2001) AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 276:28969–28975PubMedCrossRefGoogle Scholar
  46. 46.
    Castellano JM, Navarro VM, Fernandez-Fernandez R, Castano JP, Malagon MM, Aguilar E, Dieguez C, Magni P, Pinilla L, Tena-Sempere M (2006) Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropin-releasing hormone system of the rat. Mol Cell Endocrinol 257–258:75–83PubMedCrossRefGoogle Scholar
  47. 47.
    Roa J, Vigo E, Garcia-Galiano D, Castellano JM, Navarro VM, Pineda R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M (2008) Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states. Am J Physiol Endocrinol Metab 294:E1088–1096PubMedCrossRefGoogle Scholar
  48. 48.
    Seminara SB, Dipietro MJ, Ramaswamy S, Crowley WF Jr, Plant TM (2006) Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-­releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology 147:2122–2126PubMedCrossRefGoogle Scholar
  49. 49.
    Thompson EL, Murphy KG, Patterson M, Bewick GA, Stamp GW, Curtis AE, Cooke JH, Jethwa PH, Todd JF, Ghatei MA, Bloom SR (2006) Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. Am J Physiol Endocrinol Metab 291:E1074–1082PubMedCrossRefGoogle Scholar
  50. 50.
    Ramaswamy S, Seminara SB, Pohl CR, DiPietro MJ, Crowley WF Jr, Plant TM (2007) Effect of continuous intravenous administration of human metastin 45-54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology 148:3364–3370PubMedCrossRefGoogle Scholar
  51. 51.
    George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA (2011) Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab 96:E1228–1236PubMedCrossRefGoogle Scholar
  52. 52.
    Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB (2012) Kisspeptin administration to women: A window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle. J Clin Endocrinol Metab 97(8):E1458–67PubMedCrossRefGoogle Scholar
  53. 53.
    Palczewski K, Buczylko J, Kaplan MW, Polans AS, Crabb JW (1991) Mechanism of rhodopsin kinase activation. J Biol Chem 266:12949–12955PubMedGoogle Scholar
  54. 54.
    Gurevich VV, Benovic JL (1993) Visual arrestin interaction with rhodopsin. Sequential multisite binding ensures strict selectivity toward light-activated phosphorylated rhodopsin. J Biol Chem 268:11628–11638PubMedGoogle Scholar
  55. 55.
    Ferguson SS (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53:1–24PubMedGoogle Scholar
  56. 56.
    Drake MT, Shenoy SK, Lefkowitz RJ (2006) Trafficking of G protein-coupled receptors. Circ Res 99:570–582PubMedCrossRefGoogle Scholar
  57. 57.
    Gurevich VV, Gurevich EV (2006) The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol Ther 110:465–502PubMedCrossRefGoogle Scholar
  58. 58.
    Szereszewski JM, Pampillo M, Ahow MR, Offermanns S, Bhattacharya M, Babwah AV (2010) GPR54 regulates ERK1/2 activity and hypothalamic gene expression in a Galpha(q/11) and beta-arrestin-dependent manner. PLoS One 5:e12964PubMedCrossRefGoogle Scholar
  59. 59.
    Chaturvedi K, Bandari P, Chinen N, Howells RD (2001) Proteasome involvement in agonist-­induced down-regulation of mu and delta opioid receptors. J Biol Chem 276:12345–12355PubMedCrossRefGoogle Scholar
  60. 60.
    Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313PubMedCrossRefGoogle Scholar
  61. 61.
    Semple RK, Topaloglu AK (2010) The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions. Clin Endocrinol (Oxf) 72:427–435CrossRefGoogle Scholar
  62. 62.
    Sykiotis GP, Hoang XH, Avbelj M, Hayes FJ, Thambundit A, Dwyer A, Au M, Plummer L, Crowley WF Jr, Pitteloud N (2010) Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab 95:3019–3027PubMedCrossRefGoogle Scholar
  63. 63.
    Pallais JC, Au M, Pitteloud N, Seminara S, Crowley WF (1993) Isolated gonadotropin-­releasing hormone (GnRH) deficiency overview. In: Bird TD, Dolan CR, Stephens K, Adam MP, Pagon RA (eds) GeneReviews™. University of Washington, SeattleGoogle Scholar
  64. 64.
    Cariboni A, Maggi R (2006) Kallmann’s syndrome, a neuronal migration defect. Cell Mol Life Sci 63:2512–2526PubMedCrossRefGoogle Scholar
  65. 65.
    Mitchell AL, Dwyer A, Pitteloud N, Quinton R (2011) Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab 22:249–258PubMedGoogle Scholar
  66. 66.
    Bianco SD, Kaiser UB (2009) The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 5:569–576PubMedCrossRefGoogle Scholar
  67. 67.
    Wahab F, Quinton R, Seminara SB (2011) The kisspeptin signaling pathway and its role in human isolated GnRH deficiency. Mol Cell Endocrinol 346:29–36PubMedCrossRefGoogle Scholar
  68. 68.
    Wacker JL, Feller DB, Tang XB, Defino MC, Namkung Y, Lyssand JS, Mhyre AJ, Tan X, Jensen JB, Hague C (2008) Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function. J Biol Chem 283:31068–31078PubMedCrossRefGoogle Scholar
  69. 69.
    Colledge WH (2009) Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides 30:34–41PubMedCrossRefGoogle Scholar
  70. 70.
    Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE (2008) Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 28:8691–8697PubMedCrossRefGoogle Scholar
  71. 71.
    Klein KO (1999) Precocious puberty: who has it? Who should be treated? J Clin Endocrinol Metab 84:411–414PubMedCrossRefGoogle Scholar
  72. 72.
    Palmert MR, Boepple PA (2001) Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab 86:2364–2368PubMedCrossRefGoogle Scholar
  73. 73.
    Palmert MR, Hirschhorn JN (2003) Genetic approaches to stature, pubertal timing, and other complex traits. Mol Genet Metab 80:1–10PubMedCrossRefGoogle Scholar
  74. 74.
    Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP (2003) The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 24:668–693PubMedCrossRefGoogle Scholar
  75. 75.
    Aksglaede L, Sorensen K, Petersen JH, Skakkebaek NE, Juul A (2009) Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 123:e932–939PubMedCrossRefGoogle Scholar
  76. 76.
    Biro FM, Galvez MP, Greenspan LC, Succop PA, Vangeepuram N, Pinney SM, Teitelbaum S, Windham GC, Kushi LH, Wolff MS (2010) Pubertal Assessment Method and Baseline Characteristics in a Mixed Longitudinal Study of Girls. Pediatrics 126:E583–E590PubMedCrossRefGoogle Scholar
  77. 77.
    de Vries L, Kauschansky A, Shohat M, Phillip M (2004) Familial central precocious puberty suggests autosomal dominant inheritance. J Clin Endocrinol Metab 89:1794–1800PubMedCrossRefGoogle Scholar
  78. 78.
    Prete G, Couto-Silva AC, Trivin C, Brauner R (2008) Idiopathic central precocious puberty in girls: presentation factors. BMC Pediatr 8:27PubMedCrossRefGoogle Scholar
  79. 79.
    Teilmann G, Pedersen CB, Jensen TK, Skakkebaek NE, Juul A (2005) Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics 116:1323–1328PubMedCrossRefGoogle Scholar
  80. 80.
    Teles MG, Silveira LF, Tusset C, Latronico AC (2011) New genetic factors implicated in human GnRH-dependent precocious puberty: the role of kisspeptin system. Mol Cell Endocrinol 346(1–2):84–90PubMedCrossRefGoogle Scholar
  81. 81.
    Galet C, Ascoli M (2006) A constitutively active mutant of the human lutropin receptor (hLHR-L457R) escapes lysosomal targeting and degradation. Mol Endocrinol 20:2931–2945PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Suzy Drummond Carvalho Bianco
    • 1
  • Ursula B. Kaiser
    • 2
  1. 1.Department of Molecular and Cellular Pharmacology and Department of MedicineUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Division of Endocrinology, Department of MedicineHarvard Medical School/Brigham and Women’s HospitalBostonUSA

Personalised recommendations