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Cited by 2,431Hypothalamic control of reproductive hormonesGenetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesGrowth Hormone and Insulin-like Growth Factors

Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54

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de Roux, Nicolas, Genin, Emmanuelle, Carel, Jean-Claude, Matsuda, Fumihiko, Chaussain, Jean-Louis, Milgrom, Edwin·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1834399100PMC PMC196911
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Abstract

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.

    “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]

    The Abstract and Discussion report that loss of GPR54, the kisspeptin receptor, causes isolated hypogonadotropic hypogonadism in a human family. The paper does not report a mouse finding, and the Discussion says it remains unknown whether the defect acts at the hypothalamic or pituitary level; it therefore does not establish GnRH deficiency specifically. (LLM, conf=0.90)

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  • 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 [42]

  • 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 [42]

  • 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 [42]

  • Inactivating mutations in the KiSS-1 receptor were found in the homozygous state in members of two large consanguineous families with normosmic IHH in 2003.

    “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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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)
ORCID
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
DOI
10.1073/pnas.1834399100
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
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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