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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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“It is likely that the status of other modifier genes, epistatic events and environmental factors influence the final phenotype of patients with GNRHR mutations. Other Causes of IHH/KS Hypothalamus KISS1/GPR54 Although kisspeptins, which are ligands for the GPR54 (G-protein-coupled receptor 54), were originally isolate…”
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“Inactivating mutations in the kisspeptin signalling pathway cause pubertal failure, and activating mutations cause precocious puberty (de Roux et al., 2003; Seminara et al., 2003; Teles et al., 2008; Topaloglu et al., 2012).”
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“In humans, loss of function point mutations and deletions within the coding sequence of the GPR54 gene were identified in patients with idiopathic hypogonadotropic hypogonadism, a condition characterized by the absence of spontaneous pubertal development, low sex steroids and inappropriately low gonadotropins [9,10].”
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Kisspeptin Regulates Gonadotropin Genes via Immediate Early Gene Induction in Pituitary Gonadotropes
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“…et al., The discovery that loss-of-function mutations in G-proteincoupled receptor 54 gene, kisspeptin receptor (KISS1R), blocks pubertal development in humans (de Roux et al., 2003; Seminara et al., 2003) has added an entirely novel perspective regarding the regulation of puberty in vertebrates.”
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Scott, V., & Brown, C. H. (2011) · Endocrinology · doi:10.1210/en.2011-1181 · Cited by 48
Roa, J. (2013) · International Journal of Endocrinology · doi:10.1155/2013/518046 · Cited by 48
Taylor, J. E., Pampillo, M., Bhattacharya, M. M., & Babwah, A. V. (2013) · Molecular Reproduction and Development · doi:10.1002/mrd.22279 · Cited by 51
“The physiological importance of kisspeptin/KISS1R signaling is best understood as a positive regulator of the hypothalamic pituitary gonadal axis (de Roux et al., 2003; Seminara et al., 2003), although a role has also been suggested in human placentation as kisspeptin treatment has been shown to…”
BackgroundStephens, S. B. Z., Chahal, N., Munaganuru, N., Parra, R. A., & Kauffman, A. S. (2016) · Endocrinology · doi:10.1210/en.2016-1431 · Cited by 50
Metabolic Impact on the Hypothalamic Kisspeptin-Kiss1r Signaling Pathway
Wahab, F., Atika, B., Ullah, F., Shahab, M., & Behr, R. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00123 · Cited by 48
Biological Significance of Kisspeptin–Kiss 1 Receptor Signaling in the Habenula of Teleost Species
Ogawa, S., & Parhar, I. S. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00222 · Cited by 50
“In 2003, two studies reported consecutively the role of kisspeptin–KissR signaling in reproduction, particularly the control of GnRH-LH secretion during the onset of puberty in mammals (3, 4).”
BackgroundEvidence That Dynorphin Acts Upon KNDy and GnRH Neurons During GnRH Pulse Termination in the Ewe
Weems, P. W., Coolen, L. M., Hileman, S. M., Hardy, S. L., McCosh, R. B., Goodman, R. L., & Lehman, M. N. (2018) · Endocrinology · doi:10.1210/en.2018-00435 · Cited by 45
Tsutsui, K., & Ubuka, T. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100900 · Cited by 49
The genetic basis of female reproductive disorders: Etiology and clinical testing
Layman, L. C. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.02.016 · Cited by 48
“…al., 1998), GNRH1 (Bouligand et al., 2009; Chan et al., 2009)/GNRHR (de Roux et al., 1997; Layman et al., 1998), PROK2/PROKR2 (Dode et al., 2006), KISS1 (Topaloglu et al., 2012)/KISS1R (de Roux et al., 2003; Seminara et al., 2003), and TAC3 (Topaloglu et al., 2009)/TACR3 (Topaloglu et al., 2009).”
Sakamoto, K., MURATA, K., Wakabayashi, Y., Yayou, K., Ohkura, S., Takeuchi, Y., Mori, Y., & OKAMURA, H. (2012) · Journal of Reproduction and Development · doi:10.1262/jrd.2011-038 · Cited by 46
The transcriptional control of female puberty
Ojeda, S. R., Lomniczi, A., Loche, A., Matagne, V., Kaidar, G., Sandau, U. S., & Dissen, G. A. (2010) · Brain Research · doi:10.1016/j.brainres.2010.09.039 · Cited by 48
“For instance, mutations affecting different genes, including 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.”
BackgroundInformation theory and the neuropeptidergic regulation of seasonal reproduction in mammals and birds
Stevenson, T. J., & Ball, G. F. (2011) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2010.2181 · Cited by 47
Cho, S., Wang, Y., Rodríguez, M., Tan, K., Zhang, W., Luo, J., Li, D., & Liu, M. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0329 · Cited by 50
“Introduction KISS1 receptor (KISS1R, also named GPR54) coupled to its endogenous ligands, kisspeptins (KISS1 gene product), has been revealed to play a pivotal role for the onset of puberty and to suppress cancer metastasis (1-7).”
Espigares, F., Zanuy, S., & Gómez, A. (2015) · Biology of Reproduction · doi:10.1095/biolreprod.115.131029 · Cited by 47
Taziaux, M., Staphorsius, A. S., Ghatei, M. A., Bloom, S. R., Swaab, D. F., & Bakker, J. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-4175 · Cited by 47
The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders
Iwasa, T., Matsuzaki, T., Yano, K., Mayila, Y., & Irahara, M. (2018) · Endocrine Journal · doi:10.1507/endocrj.ej18-0026 · Cited by 50
Tsutsui, K., & Ubuka, T. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00662 · Cited by 47
Tena‐Sempere, M. (2013) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-396968-2.00011-7 · Cited by 51
“…publications first reported the presence of inactivating mutations of their receptor in patients with isolated hypogonadotropic hypogonadism (HH); a rare condition of lack of puberty and infertility linked to low gonadotropin and sex steroid levels (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundWhen Size Matters: A Clinical Review of Pathological Micropenis
Tsang, S. X. (2009) · Journal of Pediatric Health Care · doi:10.1016/j.pedhc.2009.05.001 · Cited by 47
Kisspeptins, new local modulators of male reproduction: A comparative overview
Meccariello, R., Fasano, S., & Pierantoni, R. (2020) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2020.113618 · Cited by 46
Assessing hypothalamic pituitary gonadal function in reproductive disorders
Koysombat, K., Dhillo, W. S., & Abbara, A. (2023) · Clinical Science · doi:10.1042/cs20220146 · Cited by 53
Scott, G., Ahmad, I., Howard, K., MacLean, D. B., Oliva, C., Warrington, S., Wilbraham, D., & WORTHINGTON, P. R. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04385.x · Cited by 46
Kisspeptin and Seasonality of Reproduction
Clarke, I. J., & Caraty, A. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-6199-9_19 · Cited by 46
Guerriero, K. A., Keen, K. L., & Terasawa, E. (2012) · Endocrinology · doi:10.1210/en.2011-1701 · Cited by 47
Hiney, J. K., Srivastava, V. K., & Dees, W. L. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.030 · Cited by 47
“The importance of the KiSS-1/GPR54 system to reproduction was revealed by the discovery that a mutation of GPR54 in human (de Roux et al., 2003; Seminara et al., 2003) and a deletion of GPR54 locus in mice (Seminara et al., 2003) caused hypogonadotropic hypogonadism and delayed puberty.”
Thompson, E. G. E., Amber, V., Stamp, G., Patterson, M., Curtis, A., Cooke, J., Appleby, G., Dhillo, W. S., Ghatei, M., Bloom, S. R., et al. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00061.x · Cited by 47
“Mice and humans lacking functional GPR54 or KiSS-1 genes do not undergo pubertal development and are infertile (Funes et al., 2003; de Roux et al., 2003; Seminara et al., 2003; Semple et al., 2005; d’Anglemont de Tassigny et al., 2007; Lapatto et al., 2007).”
BackgroundMatsuda, F., Ohkura, S., Magata, F., Munetomo, A., Chen, J., Sato, M., Inoue, N., Uenoyama, Y., & Tsukamura, H. (2019) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.14124 · Cited by 48
“ogonadism due to the spontaneous mutation of GPR54 gene (GPR54) were reported.(26,27) The effects of the blockade of kisspeptin-GPR54 signaling on repro-”
BackgroundRegulation of the Hypothalamic-Pituitary-Testicular Axis: Pathophysiology of Hypogonadism
Sharma, A., Jayasena, C. N., & Dhillo, W. S. (2022) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2021.11.010 · Cited by 50
Chachlaki, K., Messina, A., Delli, V., Leysen, V., Maurnyi, C., Huber, C., Ternier, G., Skrapits, K., Papadakis, G. E., Shruti, S., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abh2369 · Cited by 46
Seasonal breeding as a neuroendocrine model for puberty in sheep
Smith, J. T., & Clarke, I. J. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.03.007 · Cited by 46
“With respect to the control of puberty, original studies (de Roux et al., 2003; Seminara et al., 2003) strongly implicate a role for kisspeptin and its receptor and this is substantiated by studies in rodents, which suggest that kisspeptin cells in the AVPV (Clarkson et al., 2009) and the ARC…”
Trarbach, E. B., Baptista, M. T. M., Garmes, H. M., & Hackel, C. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.06103 · Cited by 46
“In addition, a second locus has been mapped on 19p13 in a large nHH consanguineous family, leading to the identification of a loss-of-function mutation in the G protein-coupled receptor 54 (GPR54) gene (Acierno et al. 2003, de Roux et al. 2003).”
Desroziers, E., Mikkelsen, J. D., Duittoz, A. H., & Franceschini, I. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02317.x · Cited by 44
Wu, S., Wilson, M. D., Busby, E. R., Isaac, E. R., & Sherwood, N. M. (2010) · Endocrinology · doi:10.1210/en.2009-0598 · Cited by 47
Song, Y., Duan, X., Chen, J., Huang, W., Zhu, Z., & Hu, W. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12251 · Cited by 46
Kisspeptin and the control of emotions, mood and reproductive behaviour
Mills, E., Dhillo, W. S., & Comninos, A. N. (2018) · Journal of Endocrinology · doi:10.1530/joe-18-0269 · Cited by 60
Leptin regulates neuropeptides associated with food intake and GnRH secretion
Guzmán, A., Hernández‐Coronado, C. G., Rosales‐Torres, A. M., & Hernandez-Medrano, J. H. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2018.07.012 · Cited by 50
A role for placental kisspeptin in β cell adaptation to pregnancy
Bowe, J. E., Hill, T. G., Hunt, K. F., Smith, L. I. F., Simpson, S., Amiel, S. A., & Jones, P. M. (2019) · JCI Insight · doi:10.1172/jci.insight.124540 · Cited by 46
Recent advances in emerging PCOS therapies
Glendining, K. A., & Campbell, R. E. (2023) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102345 · Cited by 45
Bellis, A. D., Sinisi, A. A., Conte, M., Coronella, C., Bellastella, G., Esposito, D., Pasquali, D., Ruocco, G., Bizzarro, A., & Bellastella, A. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1216 · Cited by 45
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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