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Cited by 2,557Hypothalamic control of reproductive hormonesSexual Differentiation and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

The GPR54 Gene as a Regulator of Puberty

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Seminara, Stephanie B., Messager, Sophie, Chatzidaki, Emmanouella E., Thresher, Rosemary R., Acierno, James S., Shagoury, Jenna K., Bo-Abbas, Yousef, Kuohung, Wendy +12 more·2003·New England Journal of Medicine
DOI 10.1056/nejmoa035322
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Abstract

BACKGROUND: Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. METHODS: We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein-coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. RESULTS: Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose-response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus. CONCLUSIONS: Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.

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Crossref · 10.1056/nejmoa035322

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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 [17]

  • Humans and rodents with inactivating mutations in kisspeptin or its receptor fail to progress through puberty or show normal pulsatile LH secretion.

    “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 Seminara et al., 2003

  • 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 gene were identified in individuals with isolated hypogonadotropic hypogonadism, establishing KISS1R inactivation as a cause of this disorder.

    “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 [43]

  • 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.

    “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 [43]

  • 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.

    “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 [43]

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Authors
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., Zahn, D., Dixon, J., Kaiser, U. B., Slaugenhaupt, S. A., Gusella, J. F., O'Rahilly, S., Carlton, M. B. L., Crowley, W. F., Aparicio, S. A. J. R., & Colledge, W. H.
Affiliations
  • Massachusetts General Hospital (US)
  • University of Cambridge (GB)
  • Kuwait University (KW)
  • Brigham and Women's Hospital (US)
  • Harvard University (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2003-10-23
Volume
349
Issue
17
Pages
1614-1627
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa035322
OpenAlex
W2142686356
Cited by
2,557
References
35
Citations by year
2026: 44 · 2025: 68 · 2024: 88 · 2023: 84 · 2022: 121 · 2021: 114 · 2020: 123 · 2019: 138 · 2018: 144 · 2017: 127 · 2016: 134 · 2015: 138 · 2014: 156 · 2013: 163 · 2012: 152
FWCI
44.75
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (GM61354, P01GM061354)
  • National Center for Research Resources (M01RR001066, 3M01-RR01066-22S2)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD015788, 5R01 HD15788-17, R01HD043341, U54HD029164, U54 HD28138-13, T32HD040135, T32 HD 40135, U54HD028138)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
GPR54, kisspeptin receptor, puberty onset, idiopathic hypogonadotropic hypogonadism, gonadotropin-releasing hormone, G protein-coupled receptors, autosomal recessive inheritance, inositol phosphate signaling, hypothalamic-pituitary-gonadal axis, compound heterozygosity
MeSH terms
Receptors, Kisspeptin-1, Animals, DNA Mutational Analysis, Female, Genes, Recessive, Gonadotropins, Gonads, Humans, Hypogonadism, Gonadotropin-Releasing Hormone, Lod Score, Male, Mutation, Pedigree, Phenotype, Puberty, Sexual Maturation, Receptors, Neuropeptide, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Models, Animal, Receptors, G-Protein-Coupled, Mice

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