Inactivating KISS1 Mutation and Hypogonadotropic Hypogonadism
Open accessAbstract
Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.).
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Loss-of-function mutations in the kisspeptin receptor cause GnRH deficiency in humans and mice.
“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 [18]
Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.
“Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.47,48”
From Pubertal development and regulation (2016) · cites this paper as [47]
Many other genes have been identified in association with developmental defects in GnRH neurons.
“Many other genes have been identified in association with developmental defects in GnRH neurons.”
From Pubertal development and regulation (2016) · cites this paper as [47]
These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann's syndrome.
“These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann’s syndrome (table).35,46,47,53,88–90”
From Pubertal development and regulation (2016) · cites this paper as [47]
Kisspeptin and neurokinin B are essential for pubertal development and fertility in humans.
“Moreover, two of the peptides in the hypertrophied neurons, kisspeptin and neurokinin B, are essential for pubertal development and fertility in the human (Chan et al., 2011; Topaloglu et al., 2009, 2012).”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Topaloglu et al., 2012
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Cites
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- Authors
- Topaloglu, A. K., Tello, J. A., Kotan, L. D., Ozbek, M. N., Yilmaz, M. B., Erdogan, S., Gurbuz, F., Temiz, F., Millar, R. P., & Yuksel, B.
- Affiliations
- Cukurova University (TR)
- University of Pretoria (ZA)
- University of Cape Town (ZA)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-02-16
- Volume
- 366
- Issue
- 7
- Pages
- 629-635
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2170518484
- Cited by
- 467
- References
- 24
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 22 · 2023: 20 · 2022: 26 · 2021: 40 · 2020: 34 · 2019: 42 · 2018: 32 · 2017: 29 · 2016: 36 · 2015: 37 · 2014: 46 · 2013: 43 · 2012: 20
- FWCI
- 54.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- AYBU AVESIS (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- KISS1, kisspeptin, hypogonadotropic hypogonadism, pubertal failure, loss-of-function mutations, consanguinity, kisspeptin receptor, neurokinin B, gonadotropin-releasing hormone, hypothalamic neurons
- MeSH terms
- Adolescent, Adult, Child, Consanguinity, Female, Genes, Recessive, Humans, Hypogonadism, Gonadotropin-Releasing Hormone, Male, Mutation, Pedigree, Puberty, Sequence Analysis, DNA, Kisspeptins, Genotyping Techniques
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