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International Journal of Endocrinology
Volume 2014, Article ID 649154, 13 pages
http://dx.doi.org/10.1155/2014/649154
Review Article

Central Hypogonadotropic Hypogonadism: Genetic Complexity of a Complex Disease

1Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, NOCSAE, Via Pietro Giardini 1355, 41126 Modena, Italy
2Center for Genomic Research, University of Modena and Reggio Emilia, Via Giuseppe Campi 187, 41125 Modena, Italy
3Azienda USL of Modena, Via San Giovanni del Cantone 23, 41121 Modena, Italy

Received 24 June 2014; Revised 22 August 2014; Accepted 22 August 2014; Published 1 September 2014

Academic Editor: Michael Horowitz

Copyright © 2014 Marco Marino et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Bonomi, D. V. Libri, F. Guizzardi et al., “New understandings of the genetic basis of isolated idiopathic central hypogonadism,” Asian Journal of Andrology, vol. 14, no. 1, pp. 49–56, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Messina and P. Giacobini, “Semaphorin signaling in the development and function of the gonadotropin hormone-releasing hormone system,” Frontiers in Endocrinology, vol. 4, pp. 9–23, 2013. View at Google Scholar
  3. M. E. Wierman, K. Kiseljak-Vassiliades, and S. Tobet, “Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function,” Frontiers in Neuroendocrinology, vol. 32, no. 1, pp. 43–52, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. J. von Oettingen, J. Sola Pou, L. L. Levitsky, and M. Misra, “Clinical presentation of children with premature adrenarche,” Clinical Pediatrics, vol. 51, no. 12, pp. 1140–1149, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. W. Zawatski and M. M. Lee, “Male pubertal development: are endocrine-disrupting compounds shifting the norms?” Journal of Endocrinology, vol. 218, no. 2, pp. R1–R12, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. P. J. Hornsby, “Adrenarche: a cell biological perspective,” Journal of Endocrinology, vol. 214, no. 2, pp. 113–119, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. H.-G. Kim, B. Bhagavath, and L. C. Layman, “Clinical manifestations of impaired GnRH neuron development and function,” NeuroSignals, vol. 16, no. 2-3, pp. 165–182, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. S. M. Petak, H. R. Nankin, and R. F. Spark, “American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients-2002 update,” Endocrine Practice, vol. 8, no. 6, pp. 440–456, 2002. View at Google Scholar
  9. S. Nader, “Hyperandrogenism during puberty in the development of polycystic ovary syndrome,” Fertility and Sterility, vol. 100, no. 1, pp. 39–42, 2013. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Nussey and S. Whitehead, Endocrinology: An Integrated Approach, BIOS Scientific Publishers, Oxford, UK, 2001.
  11. S. D. C. Bianco and U. B. Kaiser, “The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism,” Nature Reviews Endocrinology, vol. 5, no. 10, pp. 569–576, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. A. K. Fathi and X. Luo, “Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges,” Journal of Pediatric Endocrinology and Metabolism, vol. 26, no. 5-6, pp. 405–415, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. S. Shekhar, “Familial normosmic idiopathic hypogonadotropic hypogonadism: is there a phenotypic marker for each genetic mutation? Report of three cases and review of literature,” BMJ Case Reports, vol. 2012, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. G. P. Sykiotis, L. Plummer, V. A. Hughes et al., “Oligogenic basis of isolated gonadotropin-releasing hormone deficiency,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 34, pp. 15140–15144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. F. Brioude, J. Bouligand, S. Trabado et al., “Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype-phenotype relationships,” European Journal of Endocrinology, vol. 162, no. 5, pp. 835–851, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. E.-M. Laitinen, J. Tommiska, T. Sane, K. Vaaralahti, J. Toppari, and T. Raivio, “Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations,” PLoS ONE, vol. 7, no. 6, Article ID e39450, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. B. Kulshreshtha, R. Khadgawat, N. Gupta et al., “Progression of puberty after initiation of androgen therapy in patients with idiopathic hypogonadotropic hypogonadism,” Indian Journal of Endocrinology and Metabolism, vol. 17, no. 5, pp. 851–854, 2013. View at Google Scholar
  18. N. Pitteloud, J. S. Acierno Jr., A. U. Meysing, A. A. Dwyer, F. J. Hayes, and W. F. Crowley Jr., “Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene,” The Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 3, pp. 1317–1322, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. N. Pitteloud, P. A. Boepple, S. Decruz, S. B. Valkenburgh, W. F. Crowley Jr., and F. J. Hayes, “The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 6, pp. 2470–2475, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Raivio, J. Falardeau, A. Dwyer et al., “Reversal of idiopathic hypogonadotropic hypogonadism,” The New England Journal of Medicine, vol. 357, no. 9, pp. 863–873, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. R. S. Ribeiro, T. C. Vieira, and J. Abucham, “Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review,” European Journal of Endocrinology, vol. 156, no. 3, pp. 285–290, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. M. C. Nunes, N. S. Roy, H. M. Keyoung et al., “Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain,” Nature Medicine, vol. 9, no. 4, pp. 439–447, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. J. Altman, “Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb,” The Journal of Comparative Neurology, vol. 137, no. 4, pp. 433–457, 1969. View at Publisher · View at Google Scholar · View at Scopus
  24. F. H. Gage, “Mammalian neural stem cells,” Science, vol. 287, no. 5457, pp. 1433–1438, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. R. Quinton, W. Hasan, W. Grant et al., “Gonadotropin-releasing hormone immunoreactivity in the nasal epithelia of adults with Kallmann's syndrome and isolated hypogonadotropic hypogonadism and in the early midtrimester human fetus,” The Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 1, pp. 309–314, 1997. View at Publisher · View at Google Scholar · View at Scopus
  26. N. J. MacLusky, T. Hajszan, J. Prange-Kiel, and C. Leranth, “Androgen modulation of hippocampal synaptic plasticity,” Neuroscience, vol. 138, no. 3, pp. 957–965, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. T. S. Han and P. M. G. Bouloux, “What is the optimal therapy for young males with hypogonadotropic hypogonadism?” Clinical Endocrinology, vol. 72, no. 6, pp. 731–737, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. L. Ferreira, G. Silveira, and A. C. Latronico, “Approach to the patient with hypogonadotropic hypogonadism,” The Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 5, pp. 1781–1788, 2013. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Bhasin, G. R. Cunningham, F. J. Hayes et al., “Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 6, pp. 2536–2559, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. A. R. Lucas, C. M. Beard, W. M. O'Fallon, and L. T. Kurland, “50-Year trends in the incidence of anorexia nervosa in Rochester, Minn.: a population-based study,” American Journal of Psychiatry, vol. 148, no. 7, pp. 917–922, 1991. View at Google Scholar · View at Scopus
  31. E. M. Delemarre, B. Felius, and H. A. Delemarre-van de Waal, “Inducing puberty,” European Journal of Endocrinology, vol. 159, supplement 1, pp. S9–S15, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. R. B. Thau, M. Goldstein, Y. Yamamoto, G. N. Burrow, D. Phillips, and C. W. Bardin, “Failure of gonadotropin therapy secondary to chorionic gonadotropin-induced antibodies,” Journal of Clinical Endocrinology and Metabolism, vol. 66, no. 4, pp. 862–867, 1988. View at Publisher · View at Google Scholar · View at Scopus
  33. B. Bhagavath, R. H. Podolsky, M. Ozata et al., “Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism,” Fertility and Sterility, vol. 85, no. 3, pp. 706–713, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Marino, Genetic background of central hypogonadotropic hypogonadism [Ph.D. thesis], Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy, 2014.
  35. H.-G. Kim and L. C. Layman, “The role of CHD7 and the newly identified WDR11 gene in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome,” Molecular and Cellular Endocrinology, vol. 346, no. 1-2, pp. 74–83, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Zhang, H. Xu, T. Wang, G. Liu, and J. Liu, “The KAL1 pVal610Ile mutation is a recessive mutation causing Kallmann syndrome,” Fertility and Sterility, vol. 99, no. 6, pp. 1720–1723, 2013. View at Publisher · View at Google Scholar · View at Scopus
  37. Y. Basaran, E. Bolu, H. U. Unal et al., “Multiplex ligation dependent probe amplification analysis of KAL1, GNRH1, GNRHR, PROK2 and PROKR2 in male patients with idiopathic hypogonadotropic hypogonadism,” Endokrynologia Polska, vol. 64, no. 4, pp. 285–292, 2013. View at Google Scholar
  38. B. Franco, S. Guioli, A. Pragliola et al., “A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules,” Nature, vol. 353, no. 6344, pp. 529–536, 1991. View at Publisher · View at Google Scholar · View at Scopus
  39. C. Dodé and J.-P. Hardelin, “Kallmann syndrome,” European Journal of Human Genetics, vol. 17, no. 2, pp. 139–146, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. L. R. Montenegro, L. F. G. Silveira, C. Tusset et al., “Combined use of multiplex ligation-dependent probe amplification and automatic sequencing for identification of KAL1 defects in patients with Kallmann syndrome,” Fertility and Sterility, vol. 100, no. 3, pp. 854–859, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. E. B. Trarbach, L. G. Silveira, and A. C. Latronico, “Genetic insights into human isolated gonadotropin deficiency,” Pituitary, vol. 10, no. 4, pp. 381–391, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. J.-P. Hardelin and C. Dodé, “The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.,” Sexual Development, vol. 2, no. 4-5, pp. 181–193, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. V. Koika, P. Varnavas, H. Valavani et al., “Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH),” Gene, vol. 516, no. 1, pp. 146–151, 2013. View at Publisher · View at Google Scholar · View at Scopus
  44. L. C. Layman, “Clinical genetic testing for Kallmann syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 5, pp. 1860–1862, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. A. K. Topaloglu and L. D. Kotan, “Molecular causes of hypogonadotropic hypogonadism,” Current Opinion in Obstetrics and Gynecology, vol. 22, no. 4, pp. 264–270, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. C. Dodé and P. Rondard, “PROK2/PROKR2 signaling and Kallmann syndrome,” Frontiers in Endocrinology, vol. 4, article 19, 2013. View at Publisher · View at Google Scholar
  47. D. V. Libri, G. Kleinau, V. Vezzoli et al., “Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation of distinct intracellular pathways,” The Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 3, pp. E458–E463, 2014. View at Publisher · View at Google Scholar
  48. H.-G. Kim, I. Kurth, F. Lan et al., “Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome,” American Journal of Human Genetics, vol. 83, no. 4, pp. 511–519, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. M. C. J. Jongmans, C. M. A. van Ravenswaaij-Arts, N. Pitteloud et al., “CHD7 mutations in patients initially diagnosed with Kallmann syndrome—the clinical overlap with CHARGE syndrome,” Clinical Genetics, vol. 75, no. 1, pp. 65–71, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Vizeneux, A. Hilfiger, J. Bouligand, and et al, “Congenital hypogonadotropic hypogonadism during childhood: presentation and genetic analyses in 46 boys,” PLoS ONE, vol. 8, no. 10, Article ID e77827, 2013. View at Google Scholar
  51. J. E. H. Bergman, W. de Ronde, M. C. J. Jongmans et al., “The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 5, pp. E858–E862, 2012. View at Publisher · View at Google Scholar · View at Scopus
  52. S. D. Quaynor, H.-G. Kim, E. M. Cappello et al., “The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome,” Fertility and Sterility, vol. 96, no. 6, pp. 1424.e6–1430.e6, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. P. R. Kramer and S. Wray, “Novel gene expressed in nasal region influences outgrowth of olfactory axons and migration of luteinizing hormone-releasing hormone (LHRH) neurons,” Genes and Development, vol. 14, no. 14, pp. 1824–1834, 2000. View at Google Scholar · View at Scopus
  54. K. Miura, J. S. Acierno Jr., and S. B. Seminara, “Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH),” Journal of Human Genetics, vol. 49, no. 5, pp. 265–268, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. N. Pitteloud, R. Quinton, S. Pearce et al., “Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism,” The Journal of Clinical Investigation, vol. 117, no. 2, pp. 457–463, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. N. Xu, B. Bhagavath, H.-G. Kim et al., “NELF is a nuclear protein involved in hypothalamic GnRH neuronal migration,” Molecular and Cellular Endocrinology, vol. 319, no. 1-2, pp. 47–55, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. N. Xu, H.-G. Kim, B. Bhagavath et al., “Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome,” Fertility and Sterility, vol. 95, no. 5, pp. 1613.e7–1620.e7, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. P. Limonta and M. Manea, “Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: current options and emerging strategies,” Cancer Treatment Reviews, vol. 39, no. 6, pp. 647–663, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. Y.-M. Chan, A. de Guillebon, M. Lang-Muritano et al., “GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 28, pp. 11703–11708, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. L. Maione, F. Albarel, P. Bouchard et al., “R31C GNRH1 Mutation and Congenital Hypogonadotropic Hypogonadism,” PLoS ONE, vol. 8, no. 7, Article ID e69616, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. B. M. Cattanach, C. A. Iddon, H. M. Charlton, S. A. Chiappa, and G. Fink, “Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism,” Nature, vol. 269, no. 5626, pp. 338–340, 1977. View at Publisher · View at Google Scholar · View at Scopus
  62. A. J. Mason, J. S. Hayflick, R. T. Zoeller et al., “A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse,” Science, vol. 234, no. 4782, pp. 1366–1370, 1986. View at Google Scholar · View at Scopus
  63. K. Beate, N. Joseph, D. R. Nicolas, and K. Wolfram, “Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes,” International Journal of Endocrinology, vol. 2012, Article ID 147893, 9 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. D. Beneduzzi, E. B. Trarbach, A. C. Latronico, B. B. de Mendonca, and L. F. G. Silveira, “Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 56, no. 8, pp. 540–544, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. G. J. Hausman, C. R. Barb, and C. A. Lents, “Leptin and reproductive function,” Biochimie, vol. 94, no. 10, pp. 2075–2081, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, and J. M. Friedman, “Positional cloning of the mouse obese gene and its human homologue,” Nature, vol. 372, no. 6505, pp. 425–432, 1994. View at Publisher · View at Google Scholar · View at Scopus
  67. T. A. Dardeno, S. H. Chou, H.-S. Moon, J. P. Chamberland, C. G. Fiorenza, and C. S. Mantzoros, “Leptin in human physiology and therapeutics,” Frontiers in Neuroendocrinology, vol. 31, no. 3, pp. 377–393, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. D. Landry, F. Cloutier, and L. J. Martin, “Implications of leptin in neuroendocrine regulation of male reproduction,” Reproductive Biology, vol. 13, no. 1, pp. 1–14, 2013. View at Publisher · View at Google Scholar · View at Scopus
  69. N. E. Rance, S. J. Krajewski, M. A. Smith, M. Cholanian, and P. A. Dacks, “Neurokinin B and the hypothalamic regulation of reproduction,” Brain Research, vol. 1364, pp. 116–128, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. F. M. Pinto, C. G. Ravina, N. Subiran et al., “Autocrine regulation of human sperm motility by tachykinins,” Reproductive Biology and Endocrinology, vol. 8, article 104, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. V. M. Navarro, “Interactions between kisspeptins and neurokinin B,” Advances in Experimental Medicine and Biology, vol. 784, pp. 325–347, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Tusset, S. D. Noel, E. B. Trarbach et al., “Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 56, no. 9, pp. 646–652, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. T. Foroud, L. F. Wetherill, J. Kramer et al., “The tachykinin receptor 3 is associated with alcohol and cocaine dependence,” Alcoholism: Clinical and Experimental Research, vol. 32, no. 6, pp. 1023–1030, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Laliberte, L. DiMarzo, D. W. Morrish, and S. Kaufman, “Neurokinin B causes concentration-dependent relaxation of isolated human placental resistance vessels,” Regulatory Peptides, vol. 117, no. 2, pp. 123–126, 2004. View at Publisher · View at Google Scholar · View at Scopus
  75. N. M. Page, J. Dakour, and D. W. Morrish, “Gene regulation of neurokinin B and its receptor NK3 in late pregnancy and pre-eclampsia,” Molecular Human Reproduction, vol. 12, no. 7, pp. 427–433, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. E. Gianetti, C. Tusset, S. D. Noel et al., “TAC3/TACR3 mutations reveal preferential activation of gonadotropin- releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 6, pp. 2857–2867, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. T. Guran, G. Tolhurst, A. Bereket et al., “Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor,” The Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 10, pp. 3633–3639, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. A. K. Topaloglu, F. Reimann, M. Guclu et al., “TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction,” Nature Genetics, vol. 41, no. 3, pp. 354–358, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. J. Young, J. Bouligand, B. Francou et al., “TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans,” The Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 5, pp. 2287–2295, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. K. Skorupskaite, J. T. George, and R. A. Anderson, “The kisspeptin-GnRH pathway in human reproductive health and disease,” Human Reproduction Update, vol. 20, no. 4, pp. 485–500, 2014. View at Publisher · View at Google Scholar
  81. N. M. Page, R. J. Woods, S. M. Gardiner et al., “Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia,” Nature, vol. 405, no. 6788, pp. 797–800, 2000. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Fukami, T. Maruyama, S. Dateki, N. Sato, Y. Yoshimura, and T. Ogata, “Hypothalamic dysfunction in a female with isolated hypogonadotropic hypogonadism and compound heterozygous TACR3 mutations and clinical manifestation in her heterozygous mother,” Hormone Research in Paediatrics, vol. 73, no. 6, pp. 477–481, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. J.-H. Lee, M. E. Miele, D. J. Hicks et al., “KiSS-1, a novel human malignant melanoma metastasis-suppressor gene,” Journal of the National Cancer Institute, vol. 88, no. 23, pp. 1731–1737, 1996. View at Publisher · View at Google Scholar · View at Scopus
  84. M. F. Lippincott, C. True, and S. B. Seminara, “Use of genetic models of idiopathic hypogonadotrophic hypogonadism in mice and men to understand the mechanisms of disease,” Experimental Physiology, vol. 98, no. 11, pp. 1522–1527, 2013. View at Google Scholar
  85. F. Brioude, J. Bouligand, B. Francou et al., “Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation,” PloS ONE, vol. 8, no. 1, Article ID e53896, 2013. View at Google Scholar
  86. M. G. Martín, I. Lindberg, R. S. Solorzano-Vargas et al., “Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort,” Gastroenterology, vol. 145, no. 1, pp. 138–148, 2013. View at Publisher · View at Google Scholar · View at Scopus
  87. R. S. Jackson, J. W. M. Creemers, S. Ohagi et al., “Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene,” Nature Genetics, vol. 16, no. 3, pp. 303–306, 1997. View at Publisher · View at Google Scholar · View at Scopus
  88. I. S. Farooqi, K. Volders, R. Stanhope et al., “Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3,” The Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 9, pp. 3369–3373, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. I. S. Farooqi and S. O'Rahilly, “Genetics of obesity in humans,” Endocrine Reviews, vol. 27, no. 7, pp. 710–718, 2006. View at Publisher · View at Google Scholar · View at Scopus
  90. O. B. Chernova, A. Hunyadi, E. Malaj et al., “A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells,” Oncogene, vol. 20, no. 38, pp. 5378–5392, 2001. View at Publisher · View at Google Scholar · View at Scopus
  91. H.-G. Kim, J.-W. Ahn, I. Kurth et al., “WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome,” American Journal of Human Genetics, vol. 87, no. 4, pp. 465–479, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. J. Tornberg, G. P. Sykiotis, K. Keefe et al., “Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 28, pp. 11524–11529, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Inatani, F. Irie, A. S. Plump, M. Tessier-Lavigne, and Y. Yamaguchi, “Mammalian brain morphogenesis and midline axon guidance require heparan sulfate,” Science, vol. 302, no. 5647, pp. 1044–1046, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. A. Cariboni, K. Davidson, S. Rakic, R. Maggi, J. G. Parnavelas, and C. Ruhrberg, “Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism,” Human Molecular Genetics, vol. 20, no. 2, pp. 336–344, 2011. View at Publisher · View at Google Scholar · View at Scopus
  95. N. K. Hanchate, P. Giacobini, P. Lhuillier et al., “SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome,” PLoS Genetics, vol. 8, no. 8, Article ID e1002896, 2012. View at Publisher · View at Google Scholar · View at Scopus
  96. J. Young, C. Metay, J. Bouligand et al., “SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development,” Human Reproduction, vol. 27, no. 5, pp. 1460–1465, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. J. Känsäkoski, R. Fagerholm, E.-M. Laitinen et al., “Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism,” Pediatric Research, vol. 75, no. 5, pp. 641–644, 2014. View at Publisher · View at Google Scholar
  98. A. Messina, N. Ferraris, S. Wray et al., “Dysregulation of semaphorin7A/β1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility,” Human Molecular Genetics, vol. 20, no. 24, Article ID ddr403, pp. 4759–4774, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Berger, H. Souza, V. N. Brito, C. B. D'Alva, B. B. Mendonca, and A. C. Latronico, “Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH beta-subunit gene mutations in both sexes,” Fertility and Sterility, vol. 83, no. 2, pp. 466–470, 2005. View at Publisher · View at Google Scholar · View at Scopus
  100. L. C. Layman, A. L. A. Porto, J. Xie et al., “FSHβ gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 8, pp. 3702–3707, 2002. View at Publisher · View at Google Scholar · View at Scopus
  101. S. Basciani, M. Watanabe, S. Mariani et al., “Hypogonadism in a patient with two novel mutations of the luteinizing hormone β-subunit gene expressed in a compound heterozygous form,” The Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 9, pp. 3031–3038, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Lofrano-Porto, G. B. Barra, L. A. Giacomini et al., “Luteinizing hormone beta mutation and hypogonadism in men and women,” The New England Journal of Medicine, vol. 357, no. 9, pp. 897–904, 2007. View at Publisher · View at Google Scholar · View at Scopus
  103. H. Valdes-Socin, R. Salvi, A. F. Daly et al., “Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene,” New England Journal of Medicine, vol. 351, no. 25, pp. 2619–2625, 2004. View at Publisher · View at Google Scholar · View at Scopus
  104. J. Weiss, L. Axelrod, R. W. Whitcomb, P. E. Harris, W. F. Crowley, and J. L. Jameson, “Hypogonadism caused by a single amino acid substitution in the β subunit of luteinizing hormone,” The New England Journal of Medicine, vol. 326, no. 3, pp. 179–183, 1992. View at Google Scholar · View at Scopus
  105. D. Beneduzzi, A. K. Iyer, E. B. Trarbach et al., “Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism,” European Journal of Endocrinology, vol. 165, no. 1, pp. 145–150, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. N. L. G. Miller, R. Wevrick, and P. L. Mellon, “Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development,” Human Molecular Genetics, vol. 18, no. 2, pp. 248–260, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. N. Coré, X. Caubit, A. Metchat, A. Boned, M. Djabali, and L. Fasano, “Tshz1 is required for axial skeleton, soft palate and middle ear development in mice,” Developmental Biology, vol. 308, no. 2, pp. 407–420, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Dostal, J. Nemeckova, and R. Gaillyova, “The 18q deletion syndrome and analysis of the critical region for orofacial cleft at 18q22.3,” Journal of Cranio-Maxillofacial Surgery, vol. 37, no. 5, pp. 272–275, 2009. View at Publisher · View at Google Scholar · View at Scopus
  109. I. Feenstra, L. E. L. M. Vissers, R. J. E. Pennings et al., “Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans,” American Journal of Human Genetics, vol. 89, no. 6, pp. 813–819, 2011. View at Publisher · View at Google Scholar · View at Scopus
  110. D. Ragancokova, E. Rocca, A. M. M. Oonk et al., “TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction,” The Journal of Clinical Investigation, vol. 124, no. 3, pp. 1214–1227, 2014. View at Publisher · View at Google Scholar