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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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Items 501–600 of 1,003
Phthalates may promote female puberty by increasing kisspeptin activity
Chen, C., Chou, Y.-Y., Wu, Y.-M., Lin, C., Lin, S.-J., & Lee, C. (2013) · Human Reproduction · doi:10.1093/humrep/det325 · Cited by 75
There is Kisspeptin – And Then There is Kisspeptin
Hussain, M. A., Song, W., & Wolfe, A. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.07.008 · Cited by 75
“KISS1R was found to regulate puberty and fertility, and inactivating mutations in the KISS1R were found to be associated with reduced or absent fertility (12, 13).”
BackgroundKisspeptin signalling and its roles in humans
Tng, E.-L. (2015) · Singapore Medical Journal · doi:10.11622/smedj.2015183 · Cited by 79
The Emerging Role of Epigenetics in the Regulation of Female Puberty
Lomniczi, A., & Ojeda, S. R. (2015) · Endocrine development · doi:10.1159/000438840 · Cited by 75
Mittelman-Smith, M. A., Krajewski, S. J., McMullen, N. T., & Rance, N. E. (2016) · Endocrinology · doi:10.1210/en.2015-1740 · Cited by 74
Trudeau, V. L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00302 · Cited by 73
“Since the discovery of the link between mutations in the human gpr54 and isolated hypogonadotropic hypogonadism (de Roux et al., 2003; de Roux, 2006), the kisspeptins have become a key to the central dogma of neuroendocrine regulation of mammalian reproduction (Figure 1).”
BackgroundNiida, A., Wang, Z., Tomita, K., Oishi, S., Tamamura, H., Otaka, A., Navenot, J.-M., Broach, J. R., Peiper, S. C., & Fujii, N. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2005.09.054 · Cited by 74
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Kisspeptin signaling in the amygdala modulates reproductive hormone secretion
Comninos, A. N., Anastasovska, J., Sahuri-Arisoylu, M., Li, X., Li, S., Hu, M., Jayasena, C. N., Ghatei, M. A., Bloom, S. R., Matthews, P. M., et al. (2015) · Brain Structure and Function · doi:10.1007/s00429-015-1024-9 · Cited by 74
“…function was identified a decade ago from studies showing that humans with KISS1R or KISS1 inactivating mutations failed to go through puberty (de Roux et al. 2003; Seminara et al. 2003; Topaloglu et al. 2012), while conversely activating mutations of KISS1R or KISS1 resulted in central…”
BackgroundKiSS-1 and GPR54 at the pituitary level: Overview and recent insights
Richard, N., Corvaisier, S., Camacho, E., & Kottler, M. (2008) · Peptides · doi:10.1016/j.peptides.2008.09.015 · Cited by 73
“[5] de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E.”
Eghlidi, D. H., Haley, G. E., Noriega, N. C., Kohama, S. G., & Urbanski, H. F. (2010) · Endocrinology · doi:10.1210/en.2010-0198 · Cited by 74
“coupled receptor 54 (encoded by GPR54) (18, 19) and”
BackgroundHameed, S., Jayasena, C. N., & Dhillo, W. S. (2010) · Journal of Endocrinology · doi:10.1677/joe-10-0265 · Cited by 77
“This phenotype is remarkably similar to rodent and human models of defective kisspeptin signalling (de Roux et al. 2003, Journal of Endocrinology (2011) 208, 97–105 Downloaded from Bioscientifica.com at 11/24/2018 01:16:51PM via free access Seminara et al. 2003, d’Anglemont de Tassigny et al. 2007,…”
BackgroundResultInfluentialAbasian, Z., Rostamzadeh, A., Mohammadi, M., Hosseini, M., & Rafieian‐Kopaei, M. (2018) · Middle East Fertility Society Journal · doi:10.1016/j.mefs.2018.04.005 · Cited by 72
“Hormone changes in such models are associated with increased levels of testosterone and LH, and decreased levels of estrogen, progesterone, and FSH that are in agreement with PCOS-induced changes in different species [62].”
BackgroundMetabolic hormones are integral regulators of female reproductive health and function
Athar, F., Karmani, M., & Templeman, N. M. (2023) · Bioscience Reports · doi:10.1042/bsr20231916 · Cited by 82
Evidence that the Arcuate Nucleus Is an Important Site of Progesterone Negative Feedback in the Ewe
Goodman, R. L., Holásková, I., Nestor, C. C., Connors, J. M., Billings, H. J., Valent, M., Lehman, M. N., & Hileman, S. M. (2011) · Endocrinology · doi:10.1210/en.2011-0195 · Cited by 72
Sexual differentiation and the Kiss1 system: Hormonal and developmental considerations
Kauffman, A. S. (2008) · Peptides · doi:10.1016/j.peptides.2008.06.014 · Cited by 75
“In 2003, several groups reported that humans and mice with either spontaneous or genetically-targeted mutations in the gene for GPR54 exhibit severe deficits in reproductive function, including delayed sexual maturation, low levels of gonadal sex steroids, absent spermatogenesis and ovulation, and impaired estrous or…”
BackgroundMagee, C., Foradori, C. D., Bruemmer, J. E., Arreguin-Arevalo, J. A., McCue, P. M., Handa, R. J., Squires, E. L., & Clay, C. M. (2009) · Endocrinology · doi:10.1210/en.2008-1698 · Cited by 75
MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism
Dwyer, A. A., Raivio, T., & Pitteloud, N. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-1033 · Cited by 74
Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults
Rohayem, J., Sinthofen, N., Nieschlag, E., Kliesch, S., & Zitzmann, M. (2016) · Andrology · doi:10.1111/andr.12128 · Cited by 74
“It is possible that other gene mutations, exclusively found in normosmic CHH, including KISS1, KISS1R=GRP54 (de Roux et al., 2003; Seminara et al., 2003), TAC3, TAC3R (Topaloglu et al., 2009), GNRH1 and GNRHR (de Roux et al., 1997) may preserve higher residual HPG axis function.”
BackgroundColledge, W. H. (2004) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2004.09.008 · Cited by 72
Wacker, J. L., Feller, D. B., Tang, X.-B., DeFino, M. C., Namkung, Y., Lyssand, J. S., Mhyre, A. J., Tan, X., Jensen, J. B., & Hague, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805251200 · Cited by 71
Unravelling the mystery of puberty
Ojeda, S. R., & Lomniczi, A. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.233 · Cited by 72
Contribution of GnIH Research to the Progress of Reproductive Neuroendocrinology
Tsutsui, K., Ubuka, T., Son, Y. L., Bentley, G. E., & Kriegsfeld, L. J. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00179 · Cited by 72
A Kiss to drive rhythms in reproduction
Simonneaux, V. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14287 · Cited by 70
“…physiology by two seminal studies reporting that idiopathic hypogonadotropic hypogonadism in humans is associated with mutation of the Kiss1R gene (de Roux et al., 2003) and that a targeted deletion of the gene encoding this receptor prevented puberty onset in mice (Seminara et al., 2003).”
BackgroundGenetics of Isolated Hypogonadotropic Hypogonadism: Role of GnRH Receptor and Other Genes
Karges, B., Joseph, N., de Roux, N., & Karges, W. (2011) · International Journal of Endocrinology · doi:10.1155/2012/147893 · Cited by 73
“GPR54/KISSR mutations account for 2–5% of normosmic IHH [2, 3, 43].”
BackgroundEndocrinology of female puberty
DiVall, S. A., & Radovick, S. (2009) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e3283207937 · Cited by 72
Altered placental expression of kisspeptin and its receptor in pre-eclampsia
Cartwright, J. E., & Williams, P. J. (2012) · Journal of Endocrinology · doi:10.1530/joe-12-0091 · Cited by 70
Tooth agenesis and orofacial clefting: genetic brothers in arms?
Phan, M., Conte, F., Khandelwal, K. D., Ockeloen, C. W., Bartzela, T. N., Kleefstra, T., van Bokhoven, H., Rubini, M., Zhou, H., & Carels, C. E. L. (2016) · Human Genetics · doi:10.1007/s00439-016-1733-z · Cited by 75
“This gene is known as the causative gene of hypogonadotropic hypogonadism type 8 with or without anosmia (OMIM# 614837) (Acierno et al. 2003; de Roux et al. 2003; Brioude et al. 2013).”
BackgroundAbbara, A., Clarke, S. A., Islam, R., Prague, J., Comninos, A. N., Narayanaswamy, S., Papadopoulou, D., Roberts, R. E., Izzi‐Engbeaya, C. N., Ratnasabapathy, R., et al. (2017) · Human Reproduction · doi:10.1093/humrep/dex253 · Cited by 71
“Kisspeptin signalling is requisite for the normal initiation of puberty (de Roux et al., 2003; Seminara et al., 2003) and is obligatory for physiological ovulation in animals (Matsui et al., 2004; Caraty et al., 2007; Clarkson et al., 2008).”
BackgroundInteractions Between Kisspeptins and Neurokinin B
Navarro, V. M. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-6199-9_15 · Cited by 72
“Navarro VM, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML, Gaytan F, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54.”
BackgroundInfluentialSaadeldin, I. M., Koo, O. J., Kang, J. T., Kwon, D. K., Park, S. J., Kim, S., Moon, J. H., Oh, H. J., Jang, G., & Lee, B. C. (2011) · Reproduction Fertility and Development · doi:10.1071/rd11118 · Cited by 71
Kim, W., Jessen, H. M., Auger, A., & Terasawa, E. (2009) · Peptides · doi:10.1016/j.peptides.2008.06.005 · Cited by 70
“Since reports in 2003 showing that mutations of GPR54 were associated with infertility or delayed puberty in human patients [5,47], a large number of studies describing the role of the G-protein coupled receptor (GPR) 54 signaling in control of the LHRH-1 system have been reported.”
BackgroundMechaly, A. S., Viñas, J., & Piferrer, F. (2008) · Biology of Reproduction · doi:10.1095/biolreprod.108.072173 · Cited by 70
“Mutations of KISS1R cause autosomal recessive idiopathic hypogonadotrophic hypogonadism in humans and mice, a syndrome characterized by the impaired secretion of follicle-stimulating hormone (FSH) and LH, that leads to the formation of underdeveloped gonads and low plasma levels of the major sex steroids, testosterone…”
BackgroundInfluentialPhysiology of puberty in boys and girls and pathological disorders affecting its onset
Alotaibi, M. (2019) · Journal of Adolescence · doi:10.1016/j.adolescence.2018.12.007 · Cited by 74
Kisspeptin and the Hypothalamic Control of Reproduction: Lessons from the Human
George, J. T., & Seminara, S. B. (2012) · Endocrinology · doi:10.1210/en.2012-1429 · Cited by 69
Balasubramanian, R., & Crowley, W. F. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.07.012 · Cited by 69
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“of the hypothalamic-pituitary-gonadal axis [2,3] and loss-of-”
Marot, D., Bièche, I., Aumas, C., Esselin, S., Bouquet, C., Vacher, S., Lazennec, G., Perricaudet, M., Kuttenn, F., Lidereau, R., et al. (2007) · Endocrine Related Cancer · doi:10.1677/erc-07-0012 · Cited by 72
“Functional integrity of GPR54 is indispensable for the normal function of the gonadotropic axis in humans (de Roux et al. 2003, Seminara et al. 2003, Lanfranco et al. 2005, Semple et al. 2005, Tenenbaum-Rakover et al. 2007) as well as mice (Funes et al. 2003, Seminara et al. 2003).”
BackgroundNeuroendocrine Control of the Menstrual Cycle
Hall, J. E. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-47912-7.00007-x · Cited by 71
Moore, A. M., Coolen, L. M., & Lehman, M. N. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2117767119 · Cited by 68
“The 2003 discovery that mutations in the gene encoding the kisspeptin receptor (G protein-coupled protein 54 [GPR54]) result in hypogonadotropic hypogonadism delivered compelling evidence that kisspeptin-positive cells in the brain are required for maintaining GnRH release (3, 4).”
BackgroundGnRH-Deficient Phenotypes in Humans and Mice with Heterozygous Variants in KISS1/Kiss1
Chan, Y.-M., Broder-Fingert, S., Paraschos, S., Lapatto, R., Au, M., Hughes, V., Bianco, S. D. C., Min, L., Plummer, L., Cerrato, F., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0518 · Cited by 68
Becker, J. A. J., Mirjolet, J.-F., Bernard, J., Burgeon, E., Simons, M.-J., Vassart, G., Parmentier, M., & Libert, F. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.094 · Cited by 69
GPR54-Dependent Stimulation of Luteinizing Hormone Secretion by Neurokinin B in Prepubertal Rats
Grachev, P., Li, X. F., Lin, Y. S., Hu, M. H., Elsamani, L., Paterson, S. J., Millar, R. P., Lightman, S. L., & O’Byrne, K. T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044344 · Cited by 67
Sébert, M., Lomet, D., Saïd, S. B., Monget, P., Briant, C., Scaramuzzi, R. J., & Caraty, A. (2010) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2010.01.001 · Cited by 67
“The first evidence arose from studies showing that isolated hypogonadotropic hypogonadism syndrome was related to a genetic defect in the human GPR54 gene [1,2], and that a lack or deficiency of GPR54 caused abnormal sexual maturation and infertility in mice [2,3].”
BackgroundElectrical properties of kisspeptin neurons and their regulation of GnRH neurons
Piet, R., de Croft, S., Liu, X., & Herbison, A. E. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.05.006 · Cited by 65
Mastronardi, C. A., Smiley, G. G., Raber, J., Kusakabe, T., Kawaguchi, A., Matagne, V., Dietzel, A., Heger, S., Mungenast, A. E., Cabrera, R., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4238-06.2006 · Cited by 71
“Not only was puberty delayed in TTF1-deficient mice, but we also demonstrate that the KiSS1 gene [recently shown to play a pivotal role in the hypothalamic control of the pubertal process in humans and mice (de Roux et al., 2003; Seminara et al., 2003)] is subjected to TTF1 transcriptional control.”
BackgroundMeccariello, R., Chianese, R., Chioccarelli, T., Ciaramella, V., Fasano, S., Pierantoni, R., & Cobellis, G. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00069 · Cited by 69
Franssen, D., Gérard, A., Hennuy, B., Donneau, A., Bourguignon, J.-P., & Parent, A. (2016) · Endocrinology · doi:10.1210/en.2015-1937 · Cited by 68
“This was particularly interesting given the critical stimulating role of GPR54 and its ligand kisspeptin in the neuroendocrine control of puberty and reproduction (50, 51).”
BackgroundGlucocorticoid Regulation of Reproduction
Geraghty, A. C., & Kaufer, D. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-2895-8_11 · Cited by 68
Puberty, A Sensitive Window of Hypothalamic Development and Plasticity
Naulé, L., Maione, L., & Kaiser, U. B. (2020) · Endocrinology · doi:10.1210/endocr/bqaa209 · Cited by 86
Semaan, S. J., & Kauffman, A. S. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.11.025 · Cited by 67
“The kisspeptin system, along with NKB, is strongly implicated in pubertal development in mammals, including humans (de Roux et al., 2003; Lapatto et al., 2007; Seminara et al., 2003; Topaloglu et al., 2009, 2012; Young et al., 2010).”
Transcriptional regulation of the human KiSS1 gene
Mueller, J. K., Dietzel, A., Lomniczi, A., Loche, A., Tefs, K., Kieß, W., Danne, T., Ojeda, S. R., & Heger, S. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.04.025 · Cited by 68
“While inactivating mutations of the GPR54 gene result in hypogonadotrophic hypogonadism (HH) in humans (De Roux et al. 2003; Seminara et al. 2003; Tenenbaum-Rakover et al. 2007; Semple et al. 2005), activating mutations and certain types of polymorphisms of this gene have been reported to be…”
BackgroundGenetic insights into human isolated gonadotropin deficiency
Trarbach, E. B., Silveira, L. F. G., & Latronico, A. C. (2007) · Pituitary · doi:10.1007/s11102-007-0061-7 · Cited by 68
True, C. A., Alam, S. N., Cox, K. H., Chan, Y.-M., & Seminara, S. B. (2015) · Endocrinology · doi:10.1210/en.2014-1862 · Cited by 66
Gutiérrez‐Pascual, E., Leprince, J., Martínez‐Fuentes, A. J., Ségalas-Milazzo, I., Pineda, R., Roa, J., Durán‐Prado, M., Guilhaudis, L., Desperrois, E., Lebreton, A., et al. (2009) · Molecular Pharmacology · doi:10.1124/mol.108.053751 · Cited by 70
“In a completely different scenario, two independent groups identified in late 2003 mutations in KISS1R as the underlying cause of hypogonadotropic hypogonadism in humans (de Roux et al., 2003; Seminara et al., 2003).”
Rečnik, L.-M., Kandioller, W., & Mindt, T. L. (2020) · Molecules · doi:10.3390/molecules25163576 · Cited by 68
“The downregulation of this system is the cause of severe reproductive disorders resulting in partial or complete infertility in humans [90,91].”
BackgroundGonzález-Martı́nez, D., Hu, Y., & Bouloux, P. M. (2004) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2004.06.001 · Cited by 66
Menopause review: Emerging treatments for menopausal symptoms
Patel, B., & Dhillo, W. S. (2021) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2021.10.010 · Cited by 70
Mechaly, A. S., Viñas, J., & Piferrer, F. (2013) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2013.04.010 · Cited by 67
A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10
Curtis, A. E., Cooke, J. H., Baxter, J. E., Parkinson, J. R. C., Bataveljic, A., Ghatei, M. A., Bloom, S. R., & Murphy, K. G. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00426.2009 · Cited by 72
Helena, C. V. V., Toporikova, N., Kalil, B., Stathopoulos, A. M., Pogrebna, V. V., Carolino, R. O. G., Anselmo-Franci, J. A., & Bertram, R. (2015) · Endocrinology · doi:10.1210/en.2015-1070 · Cited by 65
“Loss of function mutations in kisspeptin cause hypogonadotropic hypogonadism, a rare genetic condition that impairs gonadotropin secretion, resulting in failure to reach puberty and infertility (9, 10).”
BackgroundIdentified GnRH neuron electrophysiology: A decade of study
Moenter, S. M. (2010) · Brain Research · doi:10.1016/j.brainres.2010.09.066 · Cited by 65
“Kisspeptin is a neuromodulator that was identified through genetic screens of patients with hypothalamic infertility [30,126].”
Recent advances in the understanding and management of delayed puberty
Wei, C. H., & Crowne, E. C. (2015) · Archives of Disease in Childhood · doi:10.1136/archdischild-2014-307963 · Cited by 67
Reproductive Neuroendocrine Pathways of Social Behavior
Parhar, I. S., Ogawa, S., & Ubuka, T. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00028 · Cited by 69
A Role for Neurokinin B in Pulsatile GnRH Secretion in the Ewe
Goodman, R. L., Coolen, L. M., & Lehman, M. N. (2013) · Neuroendocrinology · doi:10.1159/000355285 · Cited by 65
Peptides: Basic determinants of reproductive functions
Çelik, Ö., Aydın, S., Çelik, N., & Yılmaz, M. (2015) · Peptides · doi:10.1016/j.peptides.2015.05.016 · Cited by 67
“reported that loss of function mutations of the GPR54 gene are found in patients with idiopathic hypogonadotropic hypogonadism [33].”
BackgroundComplex Genetics in Idiopathic Hypogonadotropic Hypogonadism
Pitteloud, N., Durrani, S., Raivio, T., & Sykiotis, G. P. (2010) · Frontiers of hormone research · doi:10.1159/000312700 · Cited by 67
The Role of Neurokinin B Signalling in Reproductive Neuroendocrinology
Grachev, P., Millar, R. P., & O'Byrne, K. T. (2013) · Neuroendocrinology · doi:10.1159/000357734 · Cited by 65
“In particular, the neuropeptides neurokinin B (NKB) [9] and kisspeptin [10,11] have been shown to be indispensable for physiological development and function of the human reproductive system.”
BackgroundNeuroendocrine Effects of Endocrine Disruptors in Teleost Fish
Page, Y. L., Vosges, M., Servili, A., Brion, F., & Kah, O. (2011) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2011.578558 · Cited by 65
“However, the discovery in 2003 of the Kiss/GPR54 system and its roles as a major regulator of reproduction and puberty ( de Roux et al. 2003 ; Seminara et al.”
BackgroundThe roles of kisspeptin revisited: inside and outside the hypothalamus
Uenoyama, Y., Pheng, V., Tsukamura, H., & Maeda, K. (2016) · Journal of Reproduction and Development · doi:10.1262/jrd.2016-083 · Cited by 67
“The first evidence for the physiological significance of kisspeptinGPR54 signaling in the onset of puberty dates back to two independent findings of loss-of-function mutations of GPR54 in humans with hypogonadotropic hypogonadism, a pubertal failure with impaired secretion of gonadotropins [45, 46].”
BackgroundKisspeptin and Metabolism: The Brain and Beyond
Dudek, M., Ziarniak, K., & Sliwowska, J. H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00145 · Cited by 77
“Nat Rev Endocrinol (2011) 8(4):228–36.”
BackgroundInfluentialKiSS-1 and GPR54 as New Players in Gonadotropin Regulation and Puberty
Kaiser, U. B., & Kuohung, W. (2005) · Endocrine · doi:10.1385/endo:26:3:277 · Cited by 64
Kanda, S., Karigo, T., & Oka, Y. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02296.x · Cited by 64
Bond, J. P. D., Li, Q., Millar, R. P., Clarke, I. J., & Smith, J. T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057972 · Cited by 64
Semaan, S. J., Dhamija, S., Kim, J., Ku, E., & Kauffman, A. S. (2012) · Endocrinology · doi:10.1210/en.2011-1975 · Cited by 65
Prentice, L., Klausen, C., Kalloger, S. E., Köbel, M., McKinney, S. E., Santos, J. L., Kenney, C., Mehl, E., Gilks, C. B., Leung, P. C. K., et al. (2007) · BMC Medicine · doi:10.1186/1741-7015-5-33 · Cited by 67
“In the absence of functional kisspeptin [10] and GPR54 [9,11-13] neither humans nor mice undergo puberty and are unable to generate pituitary release of gonadotropins that drive sex-steroid release.”
Nakahara, T., Uenoyama, Y., Iwase, A., Oishi, S., Nakamura, S., Minabe, S., Watanabe, Y., Deura, C., Noguchi, T., Fujii, N., et al. (2013) · Journal of Reproduction and Development · doi:10.1262/jrd.2013-046 · Cited by 64
Insulin and Leptin Signaling Interact in the Mouse Kiss1 Neuron during the Peripubertal Period
Qiu, X., Dao, H., Wang, M., Heston, A., Garcia, K. M., Sangal, A., Dowling, A. R., Faulkner, L. D., Molitor, S. C., Elias, C. F., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121974 · Cited by 66
The Clinical Significance of the POLG Gene Polymorphism in Male Infertility
Krausz, C. G., Guarducci, E., Becherini, L., Degl’Innocenti, S., Gerace, L., Balercia, G., & Forti, G. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0008 · Cited by 64
Brown, R. S. E., Khant Aung, Z., Phillipps, H. R., Barad, Z., Lein, H.-J., Boehm, U., Szawka, R. E., & Grattan, D. R. (2019) · Endocrinology · doi:10.1210/en.2019-00038 · Cited by 62
The Genetic Basis of Delayed Puberty
Howard, S. R., & Dunkel, L. (2017) · Neuroendocrinology · doi:10.1159/000481569 · Cited by 63
Physiological Roles of the Kisspeptin/GPR54 System in the Neuroendocrine Control of Reproduction
Pineda, R., Aguilar, E., Pinilla, L., & Tena‐Sempere, M. (2010) · Progress in brain research · doi:10.1016/s0079-6123(08)81005-9 · Cited by 65
“This unsuspected facet of kisspeptins was exposed by the striking observation that some forms of idiopathic hypogonadotropic hypogonadism were associated with inactivating mutations of GPR54 gene (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundRedmond, J. S., Báez-Sandoval, G. M., Spell, K. M., Spencer, T. E., Lents, C. A., Williams, G. L., & Amstalden, M. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02177.x · Cited by 62
Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin
Beltramo, M., Dardente, H., Cayla, X., & Caraty, A. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.10.015 · Cited by 65
Pasquier, J., Lafont, A.-G., Leprince, J., Vaudry, H., Rousseau, K., & Dufour, S. (2011) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2011.05.019 · Cited by 64
New Gatekeepers of Reproduction: GPR54 and Its Cognate Ligand, KiSS-1
Seminara, S. B., & Kaiser, U. B. (2005) · Endocrinology · doi:10.1210/en.2005-0070 · Cited by 63
Substance P Regulates Puberty Onset and Fertility in the Female Mouse
Simavlı, S. A., Thompson, I. R., Maguire, C., Gill, J. C., Carroll, R. S., Wolfe, A., Kaiser, U. B., & Navarro, V. M. (2015) · Endocrinology · doi:10.1210/en.2014-2012 · Cited by 64
Kim, G. L., Dhillon, S. S., & Belsham, D. D. (2010) · Endocrinology · doi:10.1210/en.2010-0521 · Cited by 65
Castellano, J. M., Bentsen, A. H., Romero, M., Pineda, R., Ruíz-Pino, F., García-Galiano, D., Sanchez-Garrido, M. A., Pinilla, L., Mikkelsen, J. D., & Tena‐Sempere, M. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00081.2010 · Cited by 65
Genetics of Hypogonadotropic Hypogonadism
Topaloglu, A. K., & Kotan, L. D. (2015) · Endocrine development · doi:10.1159/000438841 · Cited by 65
Wang, L., & Moenter, S. M. (2020) · Neuroendocrinology · doi:10.1159/000503006 · Cited by 63
The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach
Voliotis, M., Li, X. F., De Burgh, R., Lass, G., Lightman, S. L., O'Byrne, K. T., & Tsaneva-Atanasova, K. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0828-19.2019 · Cited by 54
“…fertility regulation. tin has been identified as a key regulator of GnRH secretion as 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).”
BackgroundMaturation of kisspeptinergic neurons coincides with puberty onset in male rats
Overgaard, A., Ansel-Bollepalli, L., Simonneaux, V., Tena‐Sempere, M., Juul, A., & Mikkelsen, J. D. (2009) · Peptides · doi:10.1016/j.peptides.2009.11.017 · Cited by 62
Colledge, W. H. (2008) · Springer eBooks · doi:10.1007/400_2007_050 · Cited by 64
Integrative Control of Energy Balance and Reproduction in Females
García-García, R. M. (2012) · ISRN Veterinary Science · doi:10.5402/2012/121389 · Cited by 62
Normal Physiology of Hypothalamic Pituitary Regulation
Sam, S., & Frohman, L. A. (2008) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2007.10.007 · Cited by 63
“These peptides are endogenous ligands for the G protein–coupled receptor GPR54, and mutations in the gene coding for this receptor result in hypogonadotropic hypogonadism in men [93,94].”
BackgroundGPR54 Polymorphisms in Chinese Girls with Central Precocious Puberty
Luan, X., Yu, H., Wei, X., Zhou, Y., Wang, W., Li, P., Gan, X., Wei, D., & Xiao, J. (2007) · Neuroendocrinology · doi:10.1159/000107511 · Cited by 61
Pasquier, J., Lafont, A.-G., Tostivint, H., Vaudry, H., Rousseau, K., & Dufour, S. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00173 · Cited by 76
“Two years later, both kisspeptin (Kiss) and its receptor (Kissr) were demonstrated as key players of the reproductive function in mammals (de Roux et al., 2003; Funes et al., 2003; Seminara et al., 2003).”
BackgroundGonadotropin-Dependent Precocious Puberty: Neoplastic Causes and Endocrine Considerations
Stephen, M., Zage, P. E., & Waguespack, S. G. (2011) · International Journal of Pediatric Endocrinology · doi:10.1155/2011/184502 · Cited by 63
“The gene encoding kisspeptin (Kiss1) has been demonstrated to be mutated in some cases of hypogonadotropic hypogonadism [20, 21] and to be upregulated in some instances of precocious puberty [22–24].”
BackgroundWitham, E. A., Meadows, J. D., Shojaei, S., Kauffman, A. S., & Mellon, P. L. (2012) · Endocrinology · doi:10.1210/en.2012-1283 · Cited by 66
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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