Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_8F3CDBBED609
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.
Journal
eLife
Author(s)
Malone S.A., Papadakis G.E., Messina A., Mimouni NEH, Trova S., Imbernon M., Allet C., Cimino I., Acierno J., Cassatella D., Xu C., Quinton R., Szinnai G., Pigny P., Alonso-Cotchico L., Masgrau L., Maréchal J.D., Prevot V., Pitteloud N., Giacobini P.
ISSN
2050-084X (Electronic)
ISSN-L
2050-084X
Publication state
Published
Issued date
10/07/2019
Peer-reviewed
Oui
Volume
8
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.
Keywords
Adolescent, Adult, Amino Acid Sequence, Animals, Anti-Mullerian Hormone/genetics, Anti-Mullerian Hormone/metabolism, Axons/metabolism, Bone Morphogenetic Protein Receptors, Type I/metabolism, COS Cells, Cell Movement, Chlorocebus aethiops, Female, Fertility, Fetus/metabolism, Gonadotropin-Releasing Hormone/metabolism, Heterozygote, Humans, Hypogonadism/metabolism, Loss of Function Mutation, Luteinizing Hormone/metabolism, Male, Mice, Inbred C57BL, Neurons/metabolism, Olfactory Bulb/metabolism, Pedigree, Receptors, Transforming Growth Factor beta/deficiency, Receptors, Transforming Growth Factor beta/genetics, Receptors, Transforming Growth Factor beta/metabolism, Signal Transduction, Young Adult, AMH, GnRH, Kallmann's syndrome, cell migration, developmental biology, genetics, genomics, human, mouse, reproduction
Pubmed
Web of science
Open Access
Yes
Create date
21/07/2019 14:17
Last modification date
29/07/2023 5:57
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