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Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
Open accessAbstract
Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
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“loss-of-function mutations in the kisspeptin receptor cause GnRH deficiency in humans and mice (16-18).”
From Kisspeptin Overcomes GnRH Neuronal Suppression Secondary to Hyperprolactinemia in Humans (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“both humans and rodents with inactivating mutations in kisspeptin or its receptor fail to progress through puberty or show normal pulsatile LH secretion (Seminara et al., 2003;de Roux et al., 2003;Kaiser, 2015).”
From The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach (2019) · cites this paper as de Roux et al., 2003
Experimental — accuracy not yet measuredIn the citing paper
“The discovery of the kisspeptin system as a crucial component for pubertal activation of the hypothalamic-pituitary-gonadal axis occurred in 2003, when loss-of-function mutations of the KISS1R (previously known as GPR54) gene were identified in individuals with isolated hypogonadotropic hypogonadism, establishing KISS1R inactivation as a cause of this disorder (table, figure 2).42,43”
From Pubertal development and regulation (2016) · cites this paper as [42]
In the citing paper
“Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.42–45”
From Pubertal development and regulation (2016) · cites this paper as [42]
In the citing paper
“Although studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons—ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.42–44”
From Pubertal development and regulation (2016) · cites this paper as [42]
In the citing paper
“The reproductive roles of the G-protein-coupled KiSS-1 receptor (also known as GPR54, encoded by KISS1R) and its endogenous ligand, kisspeptin 1 (encoded by KISS1) were revealed in 2003 when inactivating mutations in the KiSS-1 receptor were found in the homozygous state in members of two large, consanguineous families with a history of normosmic IHH.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [34]
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The role of kisspeptin neurons in reproduction and metabolism
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“GnRH neurons constitutively express GPR54 (Irwig et al., 2004) and activation of this receptor appears to be vital for triggering the onset of puberty as humans lacking GPR 54 are hypogonadal and fail to enter puberty (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundHypothalamo-Pituitary axis and puberty
Spaziani, M., Tarantino, C., Tahani, N., Gianfrilli, D., Sbardella, E., Lenzi, A., & Radicioni, A. F. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111094 · Cited by 176
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Ojeda, S. R., Dubay, C., Lomniczi, A., Kaidar, G., Matagne, V., Sandau, U. S., & Dissen, G. A. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.12.003 · Cited by 162
“…to this question may be affirmative if one considers that rare single gene mutations, such as those affecting GNRHR (Bedecarrats and Kaiser 2007), GPR54 (de Roux et al., 2003; Seminara et al., 2003), KiSS1 (Lapatto et al., 2007), TAC3 and TACR3 (Topaloglu et al., 2008), result in pubertal failure.”
BackgroundPatisaul, H. B., Todd, K. L., Mickens, J. A., & Adewale, H. B. (2009) · NeuroToxicology · doi:10.1016/j.neuro.2009.02.010 · Cited by 162
Sex Steroids and the Control of the Kiss1 System: Developmental Roles and Major Regulatory Actions
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Kisspeptin/Kisspeptin Receptor System in the Ovary
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“It was not until 2003 that the physiological role of kisspeptins and their receptor, KISS1R in the neuroendocrine–reproductive axis was identified (26, 27), which thereafter revolutionized the field of reproductive physiology.”
BackgroundColocalization of Kisspeptin and Gonadotropin-Releasing Hormone in the Ovine Brain
Pompolo, S., Pereira, A., Estrada, K. M., & Clarke, I. J. (2005) · Endocrinology · doi:10.1210/en.2005-1123 · Cited by 147
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Guinea Pig Kisspeptin Neurons Are Depolarized by Leptin via Activation of TRPC Channels
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“GPR54 mutations in humans have been shown to cause hypogonadotropic hypogonadism and pubertal delay (7, 37, 38), and GPR54-deficient (GPR54 / ) mice have abnormal sexual development and low circulating gonadotropin concentrations and are incapable of reproducing (9).”
BackgroundLeptin action in pubertal development: recent advances and unanswered questions
Elias, C. F. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.09.002 · Cited by 145
“Lossof-function mutations in Kiss1 or GPR54/Gpr54 cause a lack of pubertal development, resulting in hypogonadotropic hypogonadism, in humans and mice (65, 66).”
BackgroundSarfati, J., Guiochon‐Mantel, A., Rondard, P., Arnulf, I., García-Piñero, A., Wołczyński, S., Brailly‐Tabard, S., Bidet, M., Ramos‐Arroyo, M. A., Mathieu, M., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0843 · Cited by 147
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Molecular Properties of Kiss1 Neurons in the Arcuate Nucleus of the Mouse
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“Kisspeptin (encoded by the Kiss1 gene) and its receptor (Kiss1r) are essential for gating the onset of puberty and regulating reproductive function in mammals (1, 2).”
BackgroundKisspeptins in Reproductive Biology: Consensus Knowledge and Recent Developments1
Roa, J., Navarro, V. M., & Tena‐Sempere, M. (2011) · Biology of Reproduction · doi:10.1095/biolreprod.111.091538 · Cited by 145
Rhythms in the endocrine system of fish: a review
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Hypothalamic Sites of Leptin Action Linking Metabolism and Reproduction
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“Kiss1 or Kiss1r loss-of-function mutations cause hypogonadotropic hypogonadism in humans and mice [”
BackgroundThe neuroanatomy of the kisspeptin system in the mammalian brain
Mikkelsen, J. D., & Simonneaux, V. (2008) · Peptides · doi:10.1016/j.peptides.2008.09.004 · Cited by 148
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“Loss of function of the GPR54 gene results in idiopathic hypogonadotrophic hypogonadism (de Roux et al., 2003; Seminara et al., 2003), while over expression of GPR54 or Kisspeptin leads to precocious puberty (Teles et al., 2011).”
BackgroundNagae, M., Uenoyama, Y., Okamoto, S., Tsuchida, H., Ikegami, K., Goto, T., Majarune, S., Nakamura, S., Sanbo, M., Hirabayashi, M., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009156118 · Cited by 146
“, GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release via activation of kisspeptin neurons in female rats.”
BackgroundGüran, T., Tolhurst, G., Bereket, A., Rocha, N., Porter, K., Turan, S., Gribble, F. M., Kotan, L. D., Akçay, T., Atay, Z., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0551 · Cited by 138
“The establishment in 2003, through a confluence of murine and human genetics, that loss of KISS1R function produces nIHH (9, 10) energized the field, and subsequent studies in humans and model organisms have demonstrated that kisspeptin, acting through KISS1R on GnRH neurons, is a highly conserved regulator of GnRH se…”
BackgroundJayasena, C. N., Abbara, A., Veldhuis, J. D., Comninos, A. N., Ratnasabapathy, R., Silva, A. D., Nijher, G. M. K., Ganiyu‐Dada, Z., Mehta, A., Todd, C., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1569 · Cited by 142
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Molecular regulation of hypothalamus–pituitary–gonads axis in males
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Epigenetic regulation of female puberty
Lomniczi, A., Wright, H., & Ojeda, S. R. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.08.003 · Cited by 136
“The critical importance of these peptides for puberty was demonstrated 10 years ago by studies in humans showing that loss of function of GPR54/KISS1R, the gene encoding the kisspeptin receptor, results in pubertal failure (Seminara et al., 2003; de Roux et al., 2003).”
BackgroundSmith, J. T., Shahab, M., Pereira, A., Pau, K. ‐. F., & Clarke, I. J. (2010) · Biology of Reproduction · doi:10.1095/biolreprod.110.085407 · Cited by 137
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“Studies in different species and animal models have highlighted the importance of Kisspeptin-Kiss1 receptor system on GnRH physiology (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundCariboni, A. M., Pimpinelli, F., Colamarino, S. A., Zaninetti, R., Piccolella, M., Rumio, C., Piva, F., Rugarli, E. I., & Maggi, R. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh309 · Cited by 137
“Moreover, mutation of FGF receptor was detected in autosomal dominant KS patients (59) and, more recently, also the loss of function of the KiSS-derived peptide GPR54 was found to be a cause of HH (60).”
BackgroundKauffman, A. S., Navarro, V. M., Kim, J. P., Clifton, D. K., & Steiner, R. A. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00461.2009 · Cited by 132
“First, humans and mice with disabling mutations or transgenic disruptions of the kisspeptin receptor gene fail to progress through puberty and remain infertile as adults (9, 14, 27, 46, 47).”
Ramaswamy, S., Seminara, S. B., & Plant, T. M. (2011) · Neuroendocrinology · doi:10.1159/000329045 · Cited by 132
KiSS-1 and Reproduction: Focus on Its Role in the Metabolic Regulation of Fertility
Tena-Sempere, M. (2006) · Neuroendocrinology · doi:10.1159/000095549 · Cited by 132
“In late 2003, our understanding of the factors involved in the central control of reproduction was revolutionized by the finding, independently reported by de Roux et al. [”
ResultJayasena, C. N., Nijher, G. M. K., Abbara, A., Murphy, K. G., Lim, A. K. P., Patel, D., Mehta, A., Todd, C., Donaldson, M., Trew, G. H., et al. (2010) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2010.204 · Cited by 134
Kisspeptin signalling in the brain: Steroid regulation in the rodent and ewe
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Kisspeptin: A key link to seasonal breeding
Revel, F. G., Ansel-Bollepalli, L., Klosen, P., Saboureau, M., Pévet, P., Mikkelsen, J. D., & Simonneaux, V. (2007) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-007-9031-7 · Cited by 135
“In late 2003, genetic studies showed unexpectedly that the phenotype of humans and mice bearing loss-of-function mutations in GPR54 matched the symptoms of idiopathic hypogonadotropic hypogonadism, with abnormal sexual development and failure to undergo puberty [41–43].”
BackgroundKisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?
Trevisan, C. M., Montagna, E., de Oliveira, R., Christofolini, D. M., Barbosa, C. P., Crandall, K. A., & Bianco, B. A. V. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000493406 · Cited by 131
Kolodziejski, P. A., Pruszyńska‐Oszmałek, E., Korek, E., Sassek, M., Szczepankiewicz, D., KACZMAREK, P., Nogowski, L., Maćkowiak, P., Nowak, K. W., Krauss, H., et al. (2018) · Physiological Research · doi:10.33549/physiolres.933467 · Cited by 130
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MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors
Pasquier, J., Kamech, N., Lafont, A.-G., Vaudry, H., Rousseau, K., & Dufour, S. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0224 · Cited by 143
Valdes‐Socin, H., Rubio-Almanza, M., Fernández-Ladreda, M. T., Debray, F. G., Bours, V., & Beckers, A. M. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00109 · Cited by 132
“Loss of function mutations in KISS1 (20) and GPR54 cause HH in mice and men (19, 21, 22).”
BackgroundLanfranco, F., Gromoll, J., von Eckardstein, S., Herding, E. M., Nieschlag, E., & Simoni, M. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.02031 · Cited by 126
Phoenixin Activates Immortalized GnRH and Kisspeptin Neurons Through the Novel Receptor GPR173
Treen, A. K., Luo, V., & Belsham, D. D. (2016) · Molecular Endocrinology · doi:10.1210/me.2016-1039 · Cited by 129
“ciated with hypogonadotropic hypogonadism and disrupted pubertal progression in both humans (6, 7) and”
BackgroundNovel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment
Abbara, A., Clarke, S. A., & Dhillo, W. S. (2018) · Endocrine Reviews · doi:10.1210/er.2017-00236 · Cited by 137
Molecular Characterization and Estrogen Regulation of Hypothalamic KISS1 Gene in the Pig1
Tomikawa, J., Homma, T., Tajima, S., Shibata, T., Inamoto, Y., Takase, K., Inoue, N., Ohkura, S., Uenoyama, Y., Maeda, K., et al. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.109.079863 · Cited by 129
The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans
Jayasena, C. N., Nijher, G. M. K., Comninos, A. N., Abbara, A., Januszewki, A., Vaal, M. L., Sriskandarajah, L., Murphy, K. G., Farzad, Z., Ghatei, M. A., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1408 · Cited by 129
Kisspeptin and energy balance in reproduction
Bond, J. P. D., & Smith, J. T. (2013) · Reproduction · doi:10.1530/rep-13-0509 · Cited by 130
Genetic determinants of pubertal timing in the general population
Gajdos, Z. K. Z., Henderson, K. D., Hirschhorn, J. N., & Palmert, M. R. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.01.038 · Cited by 121
“…hormone eceptor (GNRHR) and the G-protein coupled receptor 54 (GPR54), he G-protein coupled receptor for kisspeptins (the products of ISS1) (de Roux et al., 1997, 2003; Messager et al., 2005; Seminara t al., 2003; Shahab et al., 2005; Bedecarrats et al., 2003a,b; olczynski et al., 2003;…”
BackgroundInfluentialHrabovszky, E., Sipos, M. T., Molnár, C. S., Ciofi, P., Borsay, B. Á., Gergely, P., Herczeg, L., Bloom, S. R., Ghatei, M. A., Dhillo, W. S., et al. (2012) · Endocrinology · doi:10.1210/en.2012-1545 · Cited by 124
“379 Role of KP in the regulation of the human reproductive axis 380 In humans, KP/KISSR1 signaling plays a pivotal role in reproduction.”
BackgroundTovar, S. A., Vazquez, M. J., Navarro, V. M., Fernández-Fernández, R., Castellano, J. M., Vigo, E., Roa, J., Casanueva, F. F., Aguilar, E., Pinilla, L., et al. (2006) · Endocrinology · doi:10.1210/en.2005-1397 · Cited by 124
Kisspeptin increases GnRH mRNA expression and secretion in GnRH secreting neuronal cell lines
Novaira, H. J., Ng, Y., Wolfe, A., & Radovick, S. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.06.011 · Cited by 128
“…by the identification of the essential role of kisspeptin, the peptide product of the KiSS-1 gene, and its receptor, G-protein coupled receptor 54 (GPR54), in the neuroendocrine regulation of reproduction (de Roux et al., 2003; Funes et al., 2003; Seminara et al., 2003; Castellano et al., 2005).”
BackgroundThe role of RFamide peptides in feeding
Bechtold, D. A., & Luckman, S. M. (2007) · Journal of Endocrinology · doi:10.1677/joe-06-0069 · Cited by 124
“However, kisspeptin and its putative receptor GPR54 have been shown to play a pivotal role in the control of gonadotrophin secretion and puberty (de Roux et al. 2003, Seminara et al. 2003).”
BackgroundHypothalamic control of the male neonatal testosterone surge
Clarkson, J., & Herbison, A. E. (2016) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2015.0115 · Cited by 123
Puberty in Nonhuman Primates and Humans
Plant, T. M., & Witchel, S. F. (2006) · Elsevier eBooks · doi:10.1016/b978-012515400-0/50045-2 · Cited by 125
George, J. T., Veldhuis, J. D., Tena‐Sempere, M., Millar, R. P., & Anderson, R. A. (2012) · Clinical Endocrinology · doi:10.1111/cen.12103 · Cited by 123
Yang, J. J., Caligioni, C. S., Chan, Y.-M., & Seminara, S. B. (2012) · Endocrinology · doi:10.1210/en.2011-1949 · Cited by 122
“GNRH1/Gnrh1 (16), KISS1/Kiss1 (17, 18), KISS1R/ Kiss1r (19, 20), FGFR1/Fgfr1 (21), PROK2/Prokr2 (22, 23), and CHD7 (24, 25)] who have hypogonadotropic hypogonadism and reproductive incompetence.”
Ukena, K., & Tsutsui, K. (2004) · Mass Spectrometry Reviews · doi:10.1002/mas.20031 · Cited by 124
Takase, K., Uenoyama, Y., Inoue, N., Matsui, H., Yamada, S., Shimizu, M., Homma, T., Tomikawa, J., Kanda, S., Matsumoto, H., et al. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01868.x · Cited by 125
Dumalska, I., Wu, M., Morozova, E., Liu, R., van den Pol, A. N., & Alreja, M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1225-08.2008 · Cited by 125
“…field of neuroendocrinology has been the discovery that loss-of-function mutations of the gene encoding the G-protein-coupled receptor GPR54 are associated with autosomal recessive idiopathic hypogonadotropic hypogonadism in humans (de Roux et al., 2003; Seminara et al., 2003; Semple et al., 2005).”
BackgroundEvidence for the existence of a functional Kiss1/Kiss1 receptor pathway in fish
van Aerle, R., Kille, P., Lange, A., & Tyler, C. R. (2007) · Peptides · doi:10.1016/j.peptides.2007.10.018 · Cited by 125
New Insights into the Control of Pulsatile GnRH Release: The Role of Kiss1/Neurokinin B Neurons
Navarro, V. M. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00048 · Cited by 122
“Inactivating mutations in either KISS1 or KISS1R genes (encoding kisspeptins and the Kiss1 receptor – formerly known as GPR54, respectively) lead to hypogonadotropic hypogonadism and infertility in both humans and mice (De Roux et al., 2003; Funes et al., 2003; Seminara et al., 2003).”
BackgroundCongenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future
Kim, S. (2015) · Endocrinology and Metabolism · doi:10.3803/enm.2015.30.4.456 · Cited by 125
Schöneberg, T., & Liebscher, I. (2020) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000011 · Cited by 131
KiSS1 Suppresses Metastasis in Human Ovarian Cancer via Inhibition of Protein Kinase C Alpha
Jiang, Y., Berk, M. P., Singh, L. S., Tan, H., Yin, L., Powell, C. T., & Xu, Y. (2005) · Clinical & Experimental Metastasis · doi:10.1007/s10585-005-8186-4 · Cited by 123
“The facts that KiSS1may play a role in colonization in vivo [17, 20–23] and has a physiological role in the female reproductive system [24– 27] make KiSS1 a particularly interesting candidate for ovarian cancer metastasis suppression.”
BackgroundKisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis
Gottsch, M. L., Clifton, D. K., & Steiner, R. A. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.04.030 · Cited by 123
Cejudo-Román, A., Pinto, F. M., Dorta, I., Almeida, T. A., Hernández, M., Illanes, M., Tena‐Sempere, M., & Candenas, L. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.02.021 · Cited by 121
Neuroendocrine factors in the initiation of puberty: The emergent role of kisspeptin
Navarro, V. M., Castellano, J. M., García-Galiano, D., & Tena‐Sempere, M. (2007) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-007-9028-2 · Cited by 128
“The disclosure of the reproductive dimension of the KiSS-1/GPR54 system took place in late 2003, when two groups independently reported the presence of deletions and inactivating mutations of the GPR54 gene in patients with idiopathic hypogonadotropic hypogonadism [17, 18].”
BackgroundEvidence of a Role for Kisspeptin and Neurokinin B in Puberty of Female Sheep
Nestor, C. C., Briscoe, A. M. S., Davis, S. M., Valent, M., Goodman, R. L., & Hileman, S. M. (2012) · Endocrinology · doi:10.1210/en.2011-2009 · Cited by 118
Circadian Control of Neuroendocrine Circuits Regulating Female Reproductive Function
Williams, W. P., & Kriegsfeld, L. J. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00060 · Cited by 129
“…regulators of sexual differentiation and maturation as well as normal, adult reproductive functioning across mammalian species, including humans (de Roux et al., 2003; Funes et al., 2003; Seminara et al., 2003; Keen et al., 2008; Kauffman, 2009; Roseweir et al., 2009; Lehman et al., 2010a,b;…”
BackgroundThe gentle art of saying NO: how nitric oxide gets things done in the hypothalamus
Chachlaki, K., Garthwaite, J., & Prévot, V. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.69 · Cited by 120
The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens
Mills, E., Yang, L. Y., Nielsen, M. F., Kassem, M. S., Dhillo, W. S., & Comninos, A. N. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab015 · Cited by 136
“However, in 2003 two independent groups published reports in short succession revealing that humans with inactivating mutations of the kisspeptin receptor (GPR54/ KISS1R) resulted in failed puberty and resultant infertility (62, 63).”
BackgroundFrom KISS1 to kisspeptins: An historical perspective and suggested nomenclature
Gottsch, M. L., Clifton, D. K., & Steiner, R. A. (2008) · Peptides · doi:10.1016/j.peptides.2008.06.016 · Cited by 128
“Their genetic analysis revealed that mutations in KISS1R were associated with impaired pubertal maturation (8,49).”
BackgroundLents, C. A., Heidorn, N. L., Barb, C. R., & Ford, J. J. (2008) · Reproduction · doi:10.1530/rep-07-0502 · Cited by 128
Regulation of GPR54 Signaling by GRK2 and β-Arrestin
Pampillo, M., Camuso, N., Taylor, J. E., Szereszewski, J. M., Ahow, M. R., Zajac, M., Millar, R. P., Bhattacharya, M. M., & Babwah, A. V. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0013 · Cited by 125
Wu, M., Dumalska, I., Morozova, E., van den Pol, A. N., & Alreja, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908200106 · Cited by 117
“Mechanistically, kisspeptin is a potent activator of GnRH neurons (16–19); it enhances pituitary gonadotropin release, triggering a cascade that is essential for entering puberty (13, 20) and for maintaining ovulation and fertility (21).”
BackgroundFunctions of galanin, spexin and kisspeptin in metabolism, mood and behaviour
Mills, E., Izzi‐Engbeaya, C. N., Abbara, A., Comninos, A. N., & Dhillo, W. S. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-00438-1 · Cited by 122
Cheong, R. Y., Czieselsky, K., Porteous, R., & Herbison, A. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1776-15.2015 · Cited by 114
“…lox/lox mice Kisspeptin signaling in the brain is essential for puberty onset, estrogen feedback, and fertility in mice and humans (Seminara et al., 2003; de Roux et al., 2003; Dungan et al., 2007; d’Anglemont de Tassigny et al., 2007; Clarkson et al., 2008; Kirilov et al., 2013).”
BackgroundThe recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions
Semple, R. K., & Topaloglu, A. K. (2010) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03687.x · Cited by 117
Seasonal control of gonadotropin-inhibitory hormone (GnIH) in birds and mammals
Kriegsfeld, L. J., Ubuka, T., Bentley, G. E., & Tsutsui, K. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.12.001 · Cited by 117
“…reproductive biologists following the discovery that a loss-of-function mutations in the kisspeptin receptor, GRP54, gene are associated with a failure to attain puberty and infertility in rodents and humans (de Roux et al., 2003; Kauffman et al., 2007; Pinilla et al., 2012; Seminara et al., 2003).”
Stephens, S. B. Z., Tolson, K. P., Rouse, M. L., Poling, M. C., Hashimoto‐Partyka, M. K., Mellon, P. L., & Kauffman, A. S. (2015) · Endocrinology · doi:10.1210/en.2015-1300 · Cited by 113
Disrupted Kisspeptin Signaling in GnRH Neurons Leads to Hypogonadotrophic Hypogonadism
Novaira, H. J., Sonko, M. L., Hoffman, G. E., Koo, Y., Ko, C. J., Wolfe, A., & Radovick, S. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1319 · Cited by 118
GnRH, anosmia and hypogonadotropic hypogonadism – Where are we?
Forni, P. E., & Wray, S. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.09.004 · Cited by 122
“HH can result from defects in GnRH neuronal development [3; 4; 5], GnRH synthesis [6], release [7; 8; 9; 10] or ligand/receptor (GnRH/GnRHR) pairing [4; 11; 12; 13].”
BackgroundFunctional and evolutionary insights into vertebrate kisspeptin systems from studies of fish brain
Akazome, Y., Kanda, S., Okubo, K., & Oka, Y. (2010) · Journal of Fish Biology · doi:10.1111/j.1095-8649.2009.02496.x · Cited by 115
“Because mutations in KISS1R (GPR54) was found to be responsible for human idiopathic hypogonadotropic hypogonadism (de Roux et al., 2003; Seminara et al., 2003), and the targeted Kiss1r gene deletion brought about serious retardation of gonadal growth and infertility (Funes et al., 2003),…”
BackgroundLewkowitz-Shpuntoff, H. M., HUGHES, V. A., Plummer, L., Au, M., Doty, R. L., Seminara, S. B., Chan, Y.-M., Pitteloud, N., Crowley, W. F., & Balasubramanian, R. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2041 · Cited by 122
Clarkson, J., Han, S., Liu, X., Lee, K., & Herbison, A. E. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.01.026 · Cited by 115
Goldsammler, M., Merhi, Z. O., & Büyük, E. (2018) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-018-0366-6 · Cited by 124
Hagen, C. P., Main, K. M., Kjaergaard, S., & Juul, A. (2010) · Human Reproduction · doi:10.1093/humrep/deq291 · Cited by 114
“In primates, kisspeptin seems to be a critical upstream regulator of GnRH release in the transitions from infancy to childhood and from childhood to puberty (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundNestor, C. C., Qiu, J., Padilla, S. L., Zhang, C., Bosch, M. A., Fan, W., Aicher, S. A., Palmiter, R. D., Rønnekleiv, O. K., & Kelly, M. J. (2016) · Molecular Endocrinology · doi:10.1210/me.2016-1026 · Cited by 118
Delayed Puberty—Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries
Howard, S. R., & Dunkel, L. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00248 · Cited by 116
Metadata
- Authors
- de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E.
- Affiliations
- Institut National de la Santé et de la Recherche Médicale Unité 135, Unité de Recherches Hormones Gènes et Reproduction, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France; Institut National de la Santé et de la Recherche Médicale Unité 584, Hormone Targets, Faculté de Médecine Necker Enfants Malades, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 535, Génétique Epidémiologique et Structure des Populations Humaines, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre...
- Hôpital Necker-Enfants Malades (FR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-08-27
- Volume
- 100
- Issue
- 19
- Pages
- 10972-10976
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC196911
- OpenAlex
- W2143506157
- Cited by
- 2,431
- References
- 29
- Citations by year
- 2026: 36 · 2025: 65 · 2024: 99 · 2023: 78 · 2022: 123 · 2021: 115 · 2020: 130 · 2019: 120 · 2018: 144 · 2017: 121 · 2016: 127 · 2015: 133 · 2014: 137 · 2013: 147 · 2012: 153
- FWCI
- 45.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- isolated hypogonadotropic hypogonadism, GPR54, loss-of-function mutations, chromosome 19p13, consanguineous family, GnRH receptor, orphan G protein-coupled receptor, gonadotropic axis, aberrant splicing, follicle-stimulating hormone, luteinizing hormone
- MeSH terms
- Receptors, Kisspeptin-1, Base Sequence, Consanguinity, Female, Genotype, Humans, Hypogonadism, Male, Pedigree, DNA Primers, Receptors, Neuropeptide, Receptors, G-Protein-Coupled
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