Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism
Malone, Samuel Andrew (Jean-Pierre Aubert Research Center)
Papadakis, Georgios E. (Lausanne University Hospital)
Messina, Andrea (Lausanne University Hospital)
Mimouni, Nour El Houda (Jean-Pierre Aubert Research Center)
Trova, Sara (Jean-Pierre Aubert Research Center)
Imbernon, Monica (Jean-Pierre Aubert Research Center)
Allet, Cecile (Jean-Pierre Aubert Research Center)
Cimino, Irene (Jean-Pierre Aubert Research Center)
Acierno, James (Lausanne University Hospital)
Cassatella, Daniele (Lausanne University Hospital)
Xu, Cheng (Lausanne University Hospital)
Quinton, Richard (University of Newcastle-upon-Tyne. Institute of Genetic Medicine)
Szinnai, Gabor (University Children's Hospital Basel (Basilea, Suïssa))
Pigny, Pascal (Centre de Biologie Pathologie Génétique. Service Hormonologie Métabolisme Nutrition Oncologie)
Alonso-Cotchico, Lur (Universitat Autònoma de Barcelona. Departament de Química)
Masgrau, Laura (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Maréchal, Jean-Didier (Universitat Autònoma de Barcelona. Departament de Química)
Prevot, V. (Jean-Pierre Aubert Research Center)
Pitteloud, Nelly (Lausanne University Hospital)
Giacobini, Polo (Jean-Pierre Aubert Research Center)

Date:	2019
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.
Grants:	European Commission 725149 Ministerio de Ciencia e Innovación CTQ2017-87889-P Ministerio de Ciencia e Innovación CTQ2017-83745-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1323
Note:	Altres ajuts: Horizon 2020 Marie Sklodowska-Curie actions - European Research Fellowship (H2020-MSCA-IF-2017). Support of COST Action CM1306 is kindly acknowledged. LAC thanks Generalitat de Catalunya for her Ph.D. grant. LM thanks the 'Talent 2017' program from the Universitat Autònoma de Barcelona.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Adolescent ; Adult ; Amino acid sequence ; Animals ; Anti-mullerian hormone ; Axons ; Bone morphogenetic protein receptors, type I ; Cell movement ; Chlorocebus aethiops ; COS cells ; Female ; Fertility ; Fetus ; Gonadotropin-releasing hormone ; Heterozygote ; Humans ; Hypogonadism ; Loss of function mutation ; Luteinizing hormone ; Male ; Mice, Inbred C57BL ; Neurons ; Olfactory bulb ; Pedigree ; Receptors, transforming growth factor beta ; Signal transduction ; Young adult
Published in:	eLife, Vol. 8 (2019) , art. e47198, ISSN 2050-084X

DOI: 10.7554/eLife.47198
PMID: 31291191

36 p, 10.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles