GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency

de Roux, Nicolas

doi:10.1016/j.beem.2006.10.005

Cited by 35Hypothalamic control of reproductive hormonesSexual Differentiation and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency

de Roux, Nicolas·2006·Best Practice & Research Clinical Endocrinology & Metabolism

DOI 10.1016/j.beem.2006.10.005

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Abstract

Isolated hypogonadotropic hypogonadism (IHH) is defined by a complete or partial impaired secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the regulation of the gonadotropic axis, the gonadotropin-releasing hormone (GnRH) and its receptor have evolved as a central element in fetal life, at puberty, and for reproduction in adulthood. GnRH resistance due to GnRH receptor (GnRHR) germ-line mutations was the first genetic alteration identified in patients with IHH. GnRHR mutated receptors are associated with impaired GnRH binding, intracellular trafficking or ligand-induced signal transduction, leading to various degrees of LH and FSH deficiency. Loss-of-function mutations of the GnRH receptor account for 50% of familial cases of IHH without anosmia. In 2003, mutations of GPR54 were identified in patients with IHH, opening a new pathway in the physiological regulation of puberty and reproduction. Kisspeptins, which are the natural ligands of GPR54, are potent stimulators of the LH and FSH secretion via the control of GnRH secretion or modulation of the pituitary response to GnRH stimulation. Genotype-phenotype correlations in IHH due to GnRHR and GPR54 mutations indicate that similar mutations may lead to a variable phenotype and suggest that the pituitary might have its own pubertal maturation independent from GnRH. These two causes of IHH result in a more quantitative than qualitative defect of the gonadotropic axis activation. Molecular genetics of IHH has led to a major breakthrough in the neuroendocrine regulation of the gonadotropic axis. New insights into the understanding of the initiation of puberty and in the therapeutic management of defects of the gonadotropic axis have emerged from these studies.

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Inheritance of GNRHR mutations is autosomal recessive and most patients have compound heterozygous GNRHR mutations.
“Inheritance is autosomal recessive and most patients have compound heterozygous GNRHR mutations.70”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [70]
The increase in intracellular calcium induces pituitary luteinizing hormone and follicle-stimulating hormone secretion.
“This increase in intracellular calcium induces pituitary luteinizing hormone and follicle-stimulating hormone secretion.70”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [70]
Activation of the GnRH receptor increases calcium mobilization and stimulates influx of extracellular calcium.
“Activation of the GnRH receptor increases calcium mobilization and stimulates influx of extracellular calcium.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [70]

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Inhibition of Human Type I Gonadotropin-Releasing Hormone Receptor (GnRHR) Function by Expression of a Human Type II GnRHR Gene Fragment
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Gonadotropin-Releasing Hormone-II Messenger Ribonucleic Acid and Protein Content in the Mammalian Brain Are Modulated by Food Intake
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4 of the 80 references couldn’t be matched to a known paper.

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Puberty : ontogeny, neuroendocrinology, physiology, and disorders
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Gene structure analysis of kisspeptin-2 (Kiss2) in the Senegalese sole (Solea senegalensis): Characterization of two splice variants of Kiss2, and novel evidence for metabolic regulation of kisspeptin signaling in non-mammalian species
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A Novel Mutation in SOX2 Causes Hypogonadotropic Hypogonadism with Mild Ocular Malformation
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Kisspeptin: a new neuronal target of primer pheromones in the control of reproductive function in mammals
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GnRH receptor mutations in isolated gonadotropic deficiency
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Kisspeptin/GPR54 and idiopathic hypogonadotropic hypogonadism
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Authors: de Roux, N.
Venue: Best Practice & Research Clinical Endocrinology & Metabolism
Publisher: Elsevier BV
Published: 2006-12
Volume: 20
Issue: 4
Pages: 515-528
ISSN: 1521-690X (ISSN-L)
DOI: 10.1016/j.beem.2006.10.005
OpenAlex: W2095439208
Cited by: 35
References: 80
Citations by year: 2023: 2 · 2021: 1 · 2020: 5 · 2018: 5 · 2017: 1 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 3
FWCI: 0.27
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Best Practice & Research Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
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: isolated hypogonadotropic hypogonadism, GnRH receptor, GPR54, kisspeptin, loss-of-function mutations, gonadotropic axis, puberty onset, luteinizing hormone, follicle-stimulating hormone, genotype-phenotype correlation
MeSH terms: Receptors, Kisspeptin-1, Animals, Disease Models, Animal, Follicle Stimulating Hormone, Gene Expression Regulation, Genotype, Humans, Hypogonadism, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Phenotype, Protein Precursors, Protein Processing, Post-Translational, Receptors, LHRH, Signal Transduction, Germ-Line Mutation, Tumor Suppressor Proteins, Receptors, G-Protein-Coupled, Kisspeptins

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GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency

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