The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A comprehensive genetic map of the human genome based on 5,264 microsatellites
Dib, C., Fauré, S., Fizames, C., Samson, D. S., Drouot, N., Alain Vignal, A., Millasseau, P., Marc, S., Kazan, J., Seboun, E., et al. (1996) · Nature · doi:10.1038/380152a0 · Cited by 2,927
Parametric and nonparametric linkage analysis: a unified multipoint approach.
Kruglyak, L., Daly, M. J., Daly, M. J., & Lander, E. S. (1996) · PubMed Central · Cited by 2,883
Kotani, M., Detheux, M., Vandenbogaerde, A., Communi, D., Vanderwinden, J.-M., Le Poul, E., Brézillon, S., Tyldesley, R., Suarez-Huerta, N., Vandeput, F., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104847200 · Cited by 1,546
Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor
Ohtaki, T., Shintani, Y., Honda, S., Matsumoto, H., Hori, A., Kanehashi, K., Terao, Y., Kumano, S., Takatsu, Y., Masuda, Y., et al. (2001) · Nature · doi:10.1038/35079135 · Cited by 1,447
Faster sequential genetic linkage computations.
Cottingham, R. W., Idury, R. M., & Schäffer, A. A. (1993) · Europe PMC (PubMed Central) · Cited by 1,364
Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors
Gether, U. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.1.0390 · Cited by 1,264
KiSS-1, a Novel Human Malignant Melanoma Metastasis-Suppressor Gene
Lee, J.-H., Miele, M. E., Hicks, D. J., Phillips, K. K., Trent, J. M., Weissman, B. E., & Welch, D. R. (1996) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/88.23.1731 · Cited by 1,072
AXOR12, a Novel Human G Protein-coupled Receptor, Activated by the Peptide KiSS-1
Muir, A. I., Chamberlain, L., Elshourbagy, N. A., Michalovich, D., Moore, D. J., Calamari, A., Szekeres, P. G., Sarau, H. M., Chambers, J. K., Murdock, P. R., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102743200 · Cited by 906
Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., et al. (1991) · Nature · doi:10.1038/353529a0 · Cited by 846
Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome
Dodé, C., Levilliers, J., Dupont, J., Paepe, A. D., Dû, N. L., Soussi‐Yanicostas, N., Coimbra, R. S., Delmaghani, S., Nouaille, S., Baverel, F., et al. (2003) · Nature Genetics · doi:10.1038/ng1122 · Cited by 839
Flagged first, then by citations
Research works printed but not linked: 3
- Beranova, M., Oliveira, L. M., Bedecarrats, G. Y., Schipani, E., Vallejo, M., Ammini, A. C., Quintos, J. B., Hall, J. E., Martin, K. A., Hayes, F. J., et al. (2001) J. Clin. Endocrinol. Metab. 86, 1580–1588.11297587
- Cottingham, R. W., Jr., Idury, R. M. & Schaffer, A. A. (1993) Am. J. Hum. Genet. 53, 252–263.8317490
- Kruglyak, L., Daly, M. J., Reeve-Daly, M. P. & Lander, E. S. (1996) Am. J. Hum. Genet. 58, 1347–1363.8651312
Cited by
Sorted by citations
Items 101–200 of 1,003
Keen, K. L., Wegner, F. H., Bloom, S. R., Ghatei, M. A., & Terasawa, E. (2008) · Endocrinology · doi:10.1210/en.2008-0231 · Cited by 273
Liu, X., Lee, K., & Herbison, A. E. (2008) · Endocrinology · doi:10.1210/en.2008-0321 · Cited by 277
“I 2003, TWO GROUPS discovered that G protein-coupled receptor 54 (GPR54) was essential for puberty and subsequent fertility in humans (1, 2).”
BackgroundInfluentialPuberty and Its Measurement: A Decade in Review
Dorn, L. D., & Biro, F. M. (2011) · Journal of Research on Adolescence · doi:10.1111/j.1532-7795.2010.00722.x · Cited by 378
“Kisspeptin and KISS1 are linked as regulators to reproduction and pubertal initiation (Banerjee & Clayton, 2007; de Roux et al., 2003; Seminara et al., 2003).”
BackgroundRamaswamy, S., Seminara, S. B., Ali, B., Ciofi, P., Amin, N. A., & Plant, T. M. (2010) · Endocrinology · doi:10.1210/en.2010-0223 · Cited by 267
Isolated Familial Hypogonadotropic Hypogonadism and aGNRH1Mutation
Bouligand, J., Ghervan, C., Tello, J. A., Brailly‐Tabard, S., Salenave, S., Chanson, P., Lombès, M., Millar, R. P., Guiochon‐Mantel, A., & Young, J. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900136 · Cited by 278
Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707173104 · Cited by 264
A genetic basis for functional hypothalamic amenorrhea
Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa0911064 · Cited by 256
The Gonadotropin-Releasing Hormone Pulse Generator
Herbison, A. E. (2018) · Endocrinology · doi:10.1210/en.2018-00653 · Cited by 261
Luque, R. M., Kineman, R. D., & Tena‐Sempere, M. (2007) · Endocrinology · doi:10.1210/en.2007-0500 · Cited by 268
“However, in late 2003, two independent reports disclosed the presence of inactivating mutations and deletions of the GPR54 gene in rare forms of hypogonadotropic hypogonadism (11, 12), a phenotype similar to that of GPR54 null mice (12, 13).”
ResultExpression of KiSS-1 in Rat Ovary: Putative Local Regulator of Ovulation?
Castellano, J. M., Gaytán, M., Roa, J., Vigo, E., Navarro, V. M., Bellido, C., Diéguez, C., Aguilar, E., Sánchez‐Criado, J. E., Pellicer, A., et al. (2006) · Endocrinology · doi:10.1210/en.2006-0117 · Cited by 267
Smith, J. T., Li, Q., Yap, K. S., Shahab, M., Roseweir, A. K., Millar, R. P., & Clarke, I. J. (2011) · Endocrinology · doi:10.1210/en.2010-1225 · Cited by 254
Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling
Smith, J. T., Clifton, D. K., & Steiner, R. A. (2006) · Reproduction · doi:10.1530/rep.1.00368 · Cited by 263
“In 2003, two independent groups discovered almost simultaneously that disabling mutations of GPR54 are associated with a failure to progress through puberty and hypogonadotropic hypogonadism in man (de Roux et al. 2003, Seminara et al. 2003).”
BackgroundInteractions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat
Navarro, V. M., Castellano, J. M., McConkey, S. M., Pineda, R., Ruíz-Pino, F., Pinilla, L., Clifton, D. K., Tena‐Sempere, M., & Steiner, R. A. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00517.2010 · Cited by 251
TAC3 and TACR3 Defects Cause Hypothalamic Congenital Hypogonadotropic Hypogonadism in Humans
Young, J., Bouligand, J., Francou, B., Raffin-Sanson, M.-L., Gaillez, S., Jeanpierre, M., Grynberg, M., Kamenicky, P., Chanson, P., Brailly-Tabard, S., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2600 · Cited by 249
Castellano, J. M., Navarro, V. M., Fernández-Fernández, R., Roa, J., Vigo, E., Pineda, R., Diéguez, C., Aguilar, E., Pinilla, L., & Tena‐Sempere, M. (2006) · Diabetes · doi:10.2337/db05-1584 · Cited by 250
“Such a contention originally stems from the observation that inactivating mutations of the gene encoding GPR54 are found in patients suffering idiopathic hypogonadotropic hypogonadism (17,18).”
BackgroundMetabolic control of puberty: Roles of leptin and kisspeptins
Sanchez-Garrido, M. A., & Tena‐Sempere, M. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.01.014 · Cited by 250
The Role of Kisspeptins and GPR54 in the Neuroendocrine Regulation of Reproduction
Popa, S. M., Clifton, D. K., & Steiner, R. A. (2007) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100540 · Cited by 249
“The seminal findings of de Roux and coworkers (13) and Seminara and coworkers (14) in 2003 raised the possibility that kisspeptin might stimulate GnRH secretion by acting through GPR54.”
BackgroundInfluentialFu, L.-Y., & van den Pol, A. N. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2098-10.2010 · Cited by 243
“Mutations in GPR54 result in disruption of reproductive function in both humans and mice (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundPitteloud, N., Acierno, J. S., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600962103 · Cited by 242
Metabolic regulation of kisspeptin — the link between energy balance and reproduction
Navarro, V. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0363-7 · Cited by 240
Rance, N. E. (2009) · Peptides · doi:10.1016/j.peptides.2008.05.016 · Cited by 237
“While it is well recognized that GnRH neurons are influenced by multiple converging inputs, studies of GPR54 mutations in humans [16,93] and transgenic mice emphasize the essential nature of this circuitry in the regulation of reproduction.”
BackgroundInfluentialZhang, C., Roepke, T. A., Kelly, M. J., & Rønnekleiv, O. K. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5352-07.2008 · Cited by 239
Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition
Veldhuis, J. D., Roemmich, J. N., Richmond, E. J., & Bowers, C. Y. (2006) · Endocrine Reviews · doi:10.1210/er.2005-0006 · Cited by 236
Clarkson, J., Boon, W. C., Simpson, E. R., & Herbison, A. E. (2009) · Endocrinology · doi:10.1210/en.2008-1733 · Cited by 243
The Role of Kisspeptin in the Control of the Hypothalamic-Pituitary-Gonadal Axis and Reproduction
Xie, Q., Kang, Y., Zhang, C., Ye, X., Wang, C., Liu, J., Yu, C., Zhao, H., & Huang, D. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.925206 · Cited by 257
“In 2003, two independent studies reported patients with KISS1R gene inactivation or deletion mutation suffered familial or sporadic forms of idiopathic (or isolated) hypogonadotropic hypogonadism (iHH), which manifested as sexual immaturity and reproductive inability due to the defection of GnRH secretion (9, 106).”
BackgroundSeminara, S. B., DiPietro, M. J., Ramaswamy, S., Crowley, W. F., & Plant, T. M. (2006) · Endocrinology · doi:10.1210/en.2005-1550 · Cited by 234
Goodman, R. L., Hileman, S. M., Nestor, C. C., Porter, K. L., Connors, J. M., Hardy, S. L., Millar, R. P., Cernea, M., Coolen, L. M., & Lehman, M. N. (2013) · Endocrinology · doi:10.1210/en.2013-1331 · Cited by 234
“Moreover, because kisspeptin is essential for GnRH secretion in humans (6, 7), pulsatile GnRH secretion is normally dependent on some afferent input.”
BackgroundFelip, A., Zanuy, S., Pineda, R., Pinilla, L., Carrillo, M., Tena‐Sempere, M., & Gómez, A. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.11.017 · Cited by 232
“…of the so-called KiSS-1 system is a major breakthrough in modern Neuroendocrinology that has revolutionized the area of vertebrate reproduction (de Roux et al., 2003; Seminara et al., 2003; Matsui et al., 2004; Kaiser and Kuohung, 2005; Seminara, 2005; Seminara and Kaiser, 2005; Gottsch et al.,…”
Kanda, S., Akazome, Y., Matsunaga, T., Yamamoto, N., Yamada, S., Tsukamura, H., Maeda, K., & Oka, Y. (2008) · Endocrinology · doi:10.1210/en.2007-1503 · Cited by 234
“The lack of GPR54 leads to 10 abnormal sexual development in mice and 11 to hypogonadotropic hypogonadism in 12 humans because of low circulating 13 gonadotropin concentrations (10-12).”
BackgroundMolecular Evolution of Multiple Forms of Kisspeptins and GPR54 Receptors in Vertebrates
Lee, Y. R., Tsunekawa, K., Moon, M. J., Um, H. N., Hwang, J., Osugi, T., Otaki, N., Sunakawa, Y., Kim, K., Vaudry, H., et al. (2009) · Endocrinology · doi:10.1210/en.2008-1679 · Cited by 231
Biran, J., Ben‐Dor, S., & Levavi‐Sivan, B. (2008) · Biology of Reproduction · doi:10.1095/biolreprod.107.066266 · Cited by 248
Servili, A., Page, Y. L., Leprince, J., Caraty, A., Escobar, S., Parhar, I. S., Seong, J. Y., Vaudry, H., & Kah, O. (2011) · Endocrinology · doi:10.1210/en.2010-0948 · Cited by 226
Lemko, H. M. D., Gottsch, M. L., Zeng, H., Gragerov, A., Bergmann, J. E., Vassilatis, D. K., Clifton, D. K., & Steiner, R. A. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2748-07.2007 · Cited by 224
“The results presented here confirm previous observations that deletions of the GPR54 gene produce hypogonadotropic hypogonadism, without any other obvious phenotypic abnormalities (de Roux et al., 2003; Funes et al., 2003; Seminara et al., 2003).”
BackgroundResultDodé, C., & Hardelin, J. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.206 · Cited by 232
AgRP to Kiss1 neuron signaling links nutritional state and fertility
Padilla, S. L., Qiu, J., Nestor, C. C., Zhang, C., Smith, A. W., Whiddon, B. B., Rønnekleiv, O. K., Kelly, M. J., & Palmiter, R. D. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1621065114 · Cited by 225
“Signaling from Kiss1 and Kiss1 onto GnRH neurons is essential for normal reproductive function (25, 26); therefore, we predicted that chronic stimulation of inhibitory AgRP neurons in well-fed mice would impair fertility.”
BackgroundPineda, R., García-Galiano, D., Roseweir, A. K., Romero, M., Sanchez-Garrido, M. A., Ruíz-Pino, F., Morgan, K., Pinilla, L., Millar, R. P., & Tena‐Sempere, M. (2009) · Endocrinology · doi:10.1210/en.2009-0803 · Cited by 220
“However, despite the obvious potential of Kp as targets for therapeutic manipulation of the gonadotropic axis, the latter studies have been based mostly in protocols of single or repeated administration of agonists of GPR54, whereas development of effective Kp antagonists has remained elusive for years.”
BackgroundInfluentialThe role of kisspeptin in the control of gonadotrophin secretion
Roseweir, A. K., & Millar, R. P. (2008) · Human Reproduction Update · doi:10.1093/humupd/dmn058 · Cited by 214
“…result of gpr-54 inactivating mutations KiSS-1 was first shown to play a role in the reproductive axis in 2003, when two groups discovered that mutations in the gpr-54 receptor lead to idiopathic hypogonadotropic hypogonadism (iHH) in certain patients (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundFemale reproductive maturation in the absence of kisspeptin/GPR54 signaling
Mayer, C., & Boehm, U. (2011) · Nature Neuroscience · doi:10.1038/nn.2818 · Cited by 213
“Inactivating mutations of the human GPR54 gene are linked to hypogonadotropic hypogonadism and an absence of pubert”
BackgroundEmerging ideas about kisspeptin– GPR54 signaling in the neuroendocrine regulation of reproduction
Kauffman, A. S., Clifton, D. K., & Steiner, R. A. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.08.001 · Cited by 215
Neuroendocrine control of the onset of puberty
Plant, T. M. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2015.04.002 · Cited by 223
“In 2003, the signal observation was made that loss of function mutations of the kisspeptin receptor (KISS1R, aka GPR54) were associated with hypogonadotropism and delayed or absent puberty in both man and mice [30] [31], and it soon became apparent that the arcuate nucleus is one of two major hypothalamic sites where…”
The search for genes contributing to endometriosis risk
Montgomery, G. W., Nyholt, D. R., Zhao, Z. Z., Treloar, S. A., Painter, J. N., Missmer, S. A., Kennedy, S. H., & Zondervan, K. T. (2008) · Human Reproduction Update · doi:10.1093/humupd/dmn016 · Cited by 211
“…effects influencing reproductive pathways include mutations in KISS1 receptor (KISS1R) influencing idiopathic hypogonadotropic hypogonadism (de Roux et al., 2003; Seminara et al., 2003) and mutations in growth differentiation factor 9 (GDF9) increasing risk for dizygotic twinning (Palmer et…”
BackgroundGonadotrophin‐Releasing Hormone Pulse Generator Activity in the Hypothalamus of the Goat
Ohkura, S., Takase, K., Matsuyama, S., Mogi, K., Ichimaru, T., Wakabayashi, Y., Uenoyama, Y., Mori, Y., Steiner, R. A., Tsukamura, H., et al. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01909.x · Cited by 210
GPR54 and kisspeptin in reproduction
Tena‐Sempere, M. (2006) · Human Reproduction Update · doi:10.1093/humupd/dml023 · Cited by 213
“To date, a limited number of studies have been published describing sequence variations in the GPR54 gene responsible for familial or sporadic forms of IHH.”
BackgroundInfluentialSmith, J. T., Li, Q., Pereira, A. Z., & Clarke, I. J. (2009) · Endocrinology · doi:10.1210/en.2009-0712 · Cited by 208
Dependence of fertility on kisspeptin–Gpr54 signaling at the GnRH neuron
Kirilov, M., Clarkson, J., Liu, X., Roa, J., Campos, P., Porteous, R. W., Schütz, G., & Herbison, A. E. (2013) · Nature Communications · doi:10.1038/ncomms3492 · Cited by 206
Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2654 · Cited by 208
The Kisspeptin Receptor GPR54 Is Required for Sexual Differentiation of the Brain and Behavior
Kauffman, A. S., Park, J., McPhie-Lalmansingh, A. A., Gottsch, M. L., Bodo, C., Hohmann, J. G., Pavlova, M. N., Rohde, A. D., Clifton, D. K., Steiner, R. A., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2099-07.2007 · Cited by 210
“DOI:10.1523/JNEUROSCI.2099-07.2007 Copyright © 2007 Society for Neuroscience 0270-6474/07/278826-10$15.00/0 dotropic hypogonadism have been linked to the absence of a functional GPR54 protein (de Roux et al., 2003; Seminara et al., 2003; Semple et al., 2005).”
BackgroundInfluentialMittelman-Smith, M. A., Williams, H., Krajewski, S. J., McMullen, N. T., & Rance, N. E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211517109 · Cited by 211
“Proc Natl Acad Sci USA 107(19):8848–8853.”
A systematic review and standardized clinical validity assessment of male infertility genes
Oud, M. S., Voložonoka, L., Smits, R. M., Vissers, L. E. L. M., Ramos, L., & Veltman, J. A. (2019) · Human Reproduction · doi:10.1093/humrep/dez022 · Cited by 209
A Role for Glucocorticoids in Stress-Impaired Reproduction: Beyond the Hypothalamus and Pituitary
Whirledge, S., & Cidlowski, J. A. (2013) · Endocrinology · doi:10.1210/en.2013-1652 · Cited by 209
Neurokinin B and the hypothalamic regulation of reproduction
Rance, N. E., Krajewski, S. J., Smith, M. A., Cholanian, M., & Dacks, P. A. (2010) · Brain Research · doi:10.1016/j.brainres.2010.08.059 · Cited by 203
“Thus, the hypertrophied neurons express two mRNAs that are essential for reproduction, NKB and kisspeptin (de Roux et al., 2003; Oakley et al., 2009; Seminara et al., 2003).”
BackgroundEstrada, K. M., Clay, C. M., Pompolo, S., Smith, J. T., & Clarke, I. J. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01485.x · Cited by 211
Jayasena, C. N., Nijher, G. M. K., Chaudhri, O. B., Murphy, K. G., Ranger, A., Lim, A. K. P., Patel, D., Mehta, A., Todd, C., Ramachandran, R., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0406 · Cited by 205
Gutiérrez‐Pascual, E., Martínez‐Fuentes, A. J., Pinilla, L., Tena‐Sempere, M., Malagón, M. M., & Castano, J. P. (2007) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01558.x · Cited by 205
Li, X., Kinsey‐Jones, J. S., Cheng, Y., Knox, A. M. I., Lin, Y., Petrou, N. A., Roseweir, A. K., Lightman, S. L., Milligan, S. R., Millar, R. P., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008334 · Cited by 194
Cioppi, F., Rosta, V., & Krausz, C. G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063264 · Cited by 199
Kinsey‐Jones, J. S., Li, X. F., Knox, A. M. I., Wilkinson, E. S., Zhu, X. L., Chaudhary, A. A., Milligan, S. R., Lightman, S. L., & O’Byrne, K. T. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01807.x · Cited by 196
Li, S., Zhang, Y., Liu, Y., Huang, X., Huang, W., Lu, D., Zhu, P., Shi, Y., Cheng, C. H. K., Liu, X., et al. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0016 · Cited by 199
Kim, H.-G., Ahn, J.-W., Kurth, I., Ullmann, R., Kim, H.-T., Kulharya, A., Ha, K.-S., Itokawa, Y., Meliciani, I., Wenzel, W., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.08.018 · Cited by 195
Tsutsui, K. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.02.003 · Cited by 198
Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity
Tolson, K. P., Garcia, C. K., Yen, S., Simonds, S. E., Stefanidis, A., Lawrence, A. R., Smith, J. T., & Kauffman, A. S. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71075 · Cited by 211
G Protein–Coupled Receptor Deorphanizations
Civelli, O., Reinscheid, R. K., Zhang, Y., Wang, Z., Fredriksson, R., & Schiöth, H. B. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134548 · Cited by 199
“Furthermore, discovery of the orexin/ hypocretin and kisspeptin/GPR54 neuropeptide systems has helped reveal the long-sought basis of particular genetic disorders: The former is critically involved in the etiology of narcolepsy (64, 65), and mutations in the latter reveal its role in the regulation of gonadotropins an…”
BackgroundMittelman-Smith, M. A., Williams, H., Krajewski, S. J., Lai, J. Y., Ciofi, P., McMullen, N. T., & Rance, N. E. (2012) · Endocrinology · doi:10.1210/en.2012-1045 · Cited by 197
Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus
Maeda, K., Ohkura, S., Uenoyama, Y., Wakabayashi, Y., Oka, Y., Tsukamura, H., & Okamura, H. (2010) · Brain Research · doi:10.1016/j.brainres.2010.10.026 · Cited by 206
Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism
Stamou, M. I., & Georgopoulos, N. A. (2017) · Metabolism · doi:10.1016/j.metabol.2017.10.012 · Cited by 200
“In 2003, two independent groups utilizing endogamous pedigrees identified autosomal recessive mutations in KISS1R (formerly called GPR54) as the cause of nIHH form of IGD [70,71].”
BackgroundTsutsui, K., Bentley, G. E., Kriegsfeld, L. J., Osugi, T., Seong, J. Y., & Vaudry, H. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02018.x · Cited by 193
Moore, A. M., Coolen, L. M., Porter, D. T., Goodman, R. L., & Lehman, M. N. (2018) · Endocrinology · doi:10.1210/en.2018-00389 · Cited by 190
Leptin signaling and circuits in puberty and fertility
Elias, C. F., & Purohit, D. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1095-1 · Cited by 200
Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men
George, J. T., Veldhuis, J. D., Roseweir, A. K., Newton, C. L., Faccenda, E., Millar, R. P., & Anderson, R. A. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0089 · Cited by 186
Smith, J. T., Rao, A., Pereira, A. Z., Caraty, A., Millar, R. P., & Clarke, I. J. (2007) · Endocrinology · doi:10.1210/en.2007-1425 · Cited by 189
“sulted in hypogonadotropic hypogonadism (1, 2).”
GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism
Chan, Y.-M., de Guillebon, A., Lang‐Muritano, M., Plummer, L., Cerrato, F. E., Tsiaras, S. V., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903449106 · Cited by 196
“Mutations in GPR54 cause nIHH by interfering with the normal secretion of GnRH (18, 19), and mutations in GNRHR, which encodes the GnRH receptor, result in inability to respond to GnRH (20).”
BackgroundDiagnosis and management of precocious sexual maturation: an updated review
Cheuiche, A. V., da Silveira, L. G., de Paula, L. C. P., Lucena, I. R. S., & Silveiro, S. P. (2021) · European Journal of Pediatrics · doi:10.1007/s00431-021-04022-1 · Cited by 196
Tang, H., Liu, Y., Luo, D., Ogawa, S., Yin, Y., Li, S., Zhang, Y., Hu, W., Parhar, I. S., Lin, H., et al. (2014) · Endocrinology · doi:10.1210/en.2014-1204 · Cited by 180
Billings, H. J., Connors, J. M., Altman, S., Hileman, S. M., Holásková, I., Lehman, M. N., McManus, C. J., Nestor, C. C., Jacobs, B. H., & Goodman, R. L. (2010) · Endocrinology · doi:10.1210/en.2010-0174 · Cited by 179
“hypogonadotropic hypogonadism in humans (1, 2).”
BackgroundCastellano, J. M., Navarro, V. M., Fernández-Fernández, R., Castano, J. P., Malagón, M. M., Aguilar, E., Diéguez, C., Magni, P., Pinilla, L., & Tena‐Sempere, M. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.07.002 · Cited by 188
Defining a novel leptin–melanocortin–kisspeptin pathway involved in the metabolic control of puberty
Manfredi-Lozano, M., Roa, J., Ruíz-Pino, F., Piet, R., García-Galiano, D., Pineda, R., Zamora, A., León, S., Sanchez-Garrido, M. A., Romero‐Ruíz, A., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.08.003 · Cited by 184
Krajewski, S. J., Burke, M. C., Anderson, M. J., McMullen, N. T., & Rance, N. E. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.053 · Cited by 178
“…of function mutations in neurokinin B (NKB), the neurokinin 3 (NK3) receptor (the primary NKB receptor) or the kisspeptin receptor (GPR54) result in hypogonadotrophic hypogonadism with absence of pubertal development (Seminara et al., 2003; de Roux et al., 2003; Topaloglu et al., 2009).”
BackgroundNeuroendocrine control by kisspeptins: role in metabolic regulation of fertility
Navarro, V. M., & Tena‐Sempere, M. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.147 · Cited by 180
“In 2003, two independent studies documented the connection between the Kiss1 system and reproductive function, on the basis of findings from clinical studies”
BackgroundThe Role of Kisspeptin Signaling in Reproduction
de Tassigny, X. D., & Colledge, W. H. (2010) · Physiology · doi:10.1152/physiol.00009.2010 · Cited by 190
Cangiano, B., Swee, D. S., Quinton, R., & Bonomi, M. (2020) · Human Genetics · doi:10.1007/s00439-020-02147-1 · Cited by 184
Roa, J., Vigo, E., Castellano, J. M., Navarro, V. M., Fernández-Fernández, R., Casanueva, F. F., Diéguez, C., Aguilar, E., Pinilla, L., & Tena‐Sempere, M. (2006) · Endocrinology · doi:10.1210/en.2005-1463 · Cited by 181
“Although our previous experiments, using high (1 nmol) doses of kisspeptin-10, allowed us to define the maximal responsiveness to the peptide, in terms of gonadotropin se2870 Endocrinology, June 2006, 147(6):2864–2878 Roa et al.”
InfluentialGlucose Tolerance and Skeletal Muscle Gene Expression in Response to Alternate Day Fasting
Heilbronn, L. K., Civitarese, A. E., Bogacka, I., Smith, S. R., Hulver, M. W., & Ravussin, É. (2005) · Obesity Research · doi:10.1038/oby.2005.61 · Cited by 173
Parent, A.-S., Franssen, D., Fudvoye, J., Gérard, A., & Bourguignon, J.-P. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.12.004 · Cited by 175
The Kisspeptin/Gonadotropin-Releasing Hormone Pathway and Molecular Signaling of Puberty in Fish1
Filby, A. L., van Aerle, R., Duitman, J., & Tyler, C. R. (2007) · Biology of Reproduction · doi:10.1095/biolreprod.107.063420 · Cited by 176
Comprehensive Review on Kisspeptin and Its Role in Reproductive Disorders
Clarke, H., Dhillo, W. S., & Jayasena, C. N. (2015) · Endocrinology and Metabolism · doi:10.3803/enm.2015.30.2.124 · Cited by 180
Anatomy of the kisspeptin neural network in mammals
Lehman, M. N., Merkley, C. M., Coolen, L. M., & Goodman, R. L. (2010) · Brain Research · doi:10.1016/j.brainres.2010.09.020 · Cited by 172
“…and its related peptides are ligands for the orphan G protein-coupled receptor 54 (GPR54, now called Kiss1 receptor), mutations of which produce hypogonadotropic hypogonadism and a failure to enter puberty in humans (de Roux et al., 2003; Seminara et al., 2003) and mice (Seminara et al., 2003).”
BackgroundPhysiology of Testicular Function
Weinbauer, G. F., Luetjens, C. M., Simoni, M., & Nieschlag, E. (2010) · Springer eBooks · doi:10.1007/978-3-540-78355-8_2 · Cited by 183
“In 2003 it was discovered that loss-of-function mutations of GPR54 in the human cause failure to progress through puberty and hypogonadotropic hypogonadism (De Roux et al. 2003; Seminara et al. 2003).”
BackgroundTenenbaum-Rakover, Y., Commenges-Ducos, M., Iovane, A., Aumas, C., Admoni, O., & de Roux, N. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2147 · Cited by 169
Kisspeptins: Bridging energy homeostasis and reproduction
Castellano, J. M., Overgaard, A., Mikkelsen, J. D., & Tena‐Sempere, M. (2010) · Brain Research · doi:10.1016/j.brainres.2010.08.057 · Cited by 168
“…it is worth noting that their identification as putative modulators of the HPG axis took place only 6 years ago, when the association between inactivatingmutationsofGPR54andhypogonadotropic hypogonadism was first documented in humans and rodents (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundThe relationship between gut and adipose hormones, and reproduction
Comninos, A. N., Jayasena, C. N., & Dhillo, W. S. (2013) · Human Reproduction Update · doi:10.1093/humupd/dmt033 · Cited by 169
Neuropeptide Signaling in the Integration of Metabolism and Reproduction
Crown, A., Clifton, D. K., & Steiner, R. A. (2007) · Neuroendocrinology · doi:10.1159/000109095 · Cited by 165
García-Galiano, D., Schenau, D. V. I., León, S., Krajnc-Franken, M. A. M., Manfredi-Lozano, M., Romero‐Ruíz, A., Navarro, V. M., Gaytán, F., van Noort, P. I., Pinilla, L., et al. (2011) · Endocrinology · doi:10.1210/en.2011-1260 · Cited by 166
“The reproductive dimension of Kp was unveiled by the identification of inactivating mutations of the GPR54 gene in patients with impuberism and hypogonadotropic hypogonadism (HH) (3, 4), observations that have been recently complemented by the discovery of activating mutations of KISS1 and GPR54 genes in patients with…”
BackgroundWu, M., Dumalska, I., Morozova, E., Van Den Pol, A. N., & Alreja, M. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.166447 · Cited by 163
“Email: Meenakshi.Alreja@yale.edu Recent breakthroughs in neuroendocrinology have identified two novel hypothalamic RFamide peptides, kisspeptin (de Roux et al. 2003; Seminara et al. 2003) and gonadotropin-inhibitory hormone (GnIH; Tsutsui et al. 2000; Kriegsfeld et al. 2006), as important…”
BackgroundInfluentialTena‐Sempere, M., Felip, A., Gómez, A., Zanuy, S., & Carrillo, M. (2011) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2011.11.015 · Cited by 164
“This assumption stemmed from human and rodent data showing that inactivating mutations of GPR54 induced a state of hypogonadotropic hypogonadism [9,58].”
Neuroendocrine control of gonadotropin‐releasing hormone: Pulsatile and surge modes of secretion
Goodman, R. L., Herbison, A. E., Lehman, M. N., & Navarro, V. M. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13094 · Cited by 157
Regulation of Kiss1 Expression by Sex Steroids in the Amygdala of the Rat and Mouse
Kim, J., Semaan, S. J., Clifton, D. K., Steiner, R. A., Dhamija, S., & Kauffman, A. S. (2011) · Endocrinology · doi:10.1210/en.2010-1498 · Cited by 162
“After the discovery in 2003 that humans and mice lacking KISS1R exhibit hypogonadotropic hypogonadism and impaired puberty onset (1, 4), many reports testified to the functional significance of kisspeptin signaling in the brain to regulate mammalian reproduction.”
BackgroundLeptin Signaling in Kiss1 Neurons Arises after Pubertal Development
Cravo, R. M., Frazão, R., Perelló, M., Osborne-Lawrence, S. L., Williams, K. W., Zigman, J. M., Vianna, C., & Elias, C. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058698 · Cited by 168
Manfredi-Lozano, M., Roa, J., & Tena-Sempere, M. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.07.008 · Cited by 162
“…gene encoding kisspeptins or their receptor cause absence of puberty onset and hypogonadotropic hypogonadism in humans (Seminara et al., 2003; de Roux et al., 2003), and kisspeptins are extremely potent secretagogues of gonadotropins in different mammalian species, including humans (Pinilla et…”
BackgroundKisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization
Jayasena, C. N., Abbara, A., Comninos, A. N., Nijher, G. M. K., Christopoulos, G., Narayanaswamy, S., Izzi‐Engbeaya, C. N., Sridharan, M., Mason, A. J., Warwick, J., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75730 · Cited by 164
“Kisspeptin signaling is obligatory for mammalian fertility (4–6), and exogenous kisspeptin administration potently stimulates endogenous reproductive hormones in all mammalian species studied to date (9, 11–24 , 28 ).”
Fukusumi, S., Fujii, R., & Hinuma, S. (2006) · Peptides · doi:10.1016/j.peptides.2005.06.031 · Cited by 166
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
