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

Samuel Andrew Malone, Georgios E. Papadakis, Andrea Messina, Nour El Houda Mimouni, Sara Trova, Monica Imbernon, Cecile Allet, Irene Cimino, James Acierno, Daniele Cassatella, Cheng Xu, Richard Quinton, Gabor Szinnai, Pascal Pigny, Lur Alonso-Cotchico, Laura Masgrau, Jean Didier Maréchal, Vincent Prevot, Nelly Pitteloud, Paolo Giacobini

Research output: Contribution to journalArticleResearch

18 Citations (Scopus)

Abstract

© Malone et al. 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.
Original languageEnglish
Article numbere47198
JournaleLife
Volume8
DOIs
Publication statusPublished - 1 Jul 2019

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