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Elife. 2019 Jul 10;8. pii: e47198. doi: 10.7554/eLife.47198.

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

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Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172, Lille, France.
University of Lille, FHU 1, 000 Days for Health, Lille, France.
Faculty of Biology and Medicine, Service of Endocrinology, Diabetology and Metabolism, University Hospital, Lausanne, Switzerland.
Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom.
Pediatric Endocrinology and Diabetology, University of Basel Children's Hospital, Basel, Switzerland.
CHU Lille, Laboratoire de Biochimie et Hormonologie, Centre de Biologie Pathologie, Lille, France.
Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.


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.


AMH; GnRH; Kallmann's syndrome; cell migration; developmental biology; genetics; genomics; human; mouse; reproduction

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