A GPR54 -Activating Mutation in a Patient with Central Precocious Puberty
Open accessAbstract
Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis. In girls, this condition is most often idiopathic. Recently, a G protein-coupled receptor, GPR54, and its ligand, kisspeptin, were described as an excitatory neuroregulator system for the secretion of gonadotropin-releasing hormone (GnRH). In this study, we have identified an autosomal dominant GPR54 mutation--the substitution of proline for arginine at codon 386 (Arg386Pro)--in an adopted girl with idiopathic central precocious puberty (whose biologic family was not available for genetic studies). In vitro studies have shown that this mutation leads to prolonged activation of intracellular signaling pathways in response to kisspeptin. The Arg386Pro mutant appears to be associated with central precocious puberty.
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A non-constitutively activating mutation in KISS1R was the first identified genetic cause of central precocious puberty, reported in an adopted girl with breast development with slow progression that had first been noted at birth and that progressed at age 7 years.
“A non-constitutively activating mutation in KISS1R was the first identified genetic cause of central precocious puberty, reported in an adopted girl with breast development with slow progression that had first been noted at birth and that progressed at age 7 years.49”
From Pubertal development and regulation (2016) · cites this paper as [49]
The gain-of-function mutation in the KiSS-1 receptor causing central precocious puberty was not due to constitutive activation but to a reduced rate of receptor desensitization.
“The gain-of-function in this case was not achieved by constitutive activation of the KiSS-1 receptor. Instead, the apparent ‘activation’ of the receptor was the result of a reduced rate of receptor desensitization.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [53]
The first identifiable genetic cause of central precocious puberty was recognized as a gain-of-function mutation in the KiSS-1 receptor.
“The key role of the KiSS-1 receptor in the regulation of the onset of puberty was recently reinforced when the first identifiable genetic cause of central precocious puberty was recognized as a gain-of-function mutation in the receptor.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [53]
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References 27 · Cited by 572
Research works printed but not linked: 2
- Terasawa E, Fernandez DL. Neurobio- logical mechanisms of the onset of pu- berty in primates. Endocr Rev 2001;22:111- 51.
- de Vries L, Kauschansky A, Shohat M, Phillip M. Familial central precocious pu- berty suggests autosomal dominant in- heritance. J Clin Endocrinol Metab 2004; 89:1794-800.
- Authors
- Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., & Latronico, A. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Universidade de São Paulo (BR)
- Boston University (US)
- Harvard University (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-02-14
- Volume
- 358
- Issue
- 7
- Pages
- 709-715
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2859966
- OpenAlex
- W2013104189
- Cited by
- 572
- References
- 27
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 25 · 2023: 28 · 2022: 32 · 2021: 37 · 2020: 27 · 2019: 32 · 2018: 33 · 2017: 24 · 2016: 38 · 2015: 34 · 2014: 46 · 2013: 35 · 2012: 32
- FWCI
- 46.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD28138, 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
- central precocious puberty, GPR54, kisspeptin, G protein-coupled receptors, kisspeptin receptor, GnRH secretion, hypothalamic-pituitary-gonadal axis, autosomal dominant inheritance, intracellular signaling, idiopathic precocious puberty
- MeSH terms
- Receptors, Kisspeptin-1, Amino Acid Sequence, Child, Female, Genes, Dominant, Heterozygote, Humans, Inositol Phosphates, Molecular Sequence Data, Phosphorylation, Puberty, Precocious, Signal Transduction, Point Mutation, Sequence Analysis, DNA, Tumor Suppressor Proteins, Receptors, G-Protein-Coupled, Extracellular Signal-Regulated MAP Kinases, Kisspeptins
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