Universitat Autònoma de Barcelona
Malone, Samuel Andrew
Papadakis, Georgios E.
Messina, Andrea
Mimouni, Nour El Houda
Trova, Sara
Imbernón, Mónica
Allet, Cecile
Cimino, Irene
Acierno, James
Cassatella, Daniele
Xu, Cheng
Quinton, Richard
Szinnai, Gabor
Pigny, Pascal
Alonso-Cotchico, Lur
Masgrau, Laura
Maréchal, Jean-Didier
Prevot, V.
Pitteloud, Nelly
Giacobini, Polo
2019
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.
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
English
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
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
eLife ; Vol. 8 (2019), art. e47198
open access
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