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.
Elife. 2019 Jul 10;8:e47198. doi: 10.7554/eLife.47198.
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 () and its receptor, , 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 -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.
先天性低促性腺激素性性腺功能减退症（CHH）是一种由于促性腺激素释放激素（GnRH）缺乏导致青春期缺失和不育的病症，常伴有嗅觉缺失（卡尔曼综合征，KS）。我们通过全外显子组测序在 3%的 CHH 先证者中发现了抗苗勒管激素（AMH）及其受体 的功能丧失性杂合突变。我们表明，在胚胎发育过程中，AMH 在小鼠和人类胎儿的 GnRH 神经元迁移中表达，并揭示了 AMH 作为 GnRH 神经元促运动因子的新功能。- 缺陷小鼠的病理组织学分析显示外周嗅觉系统发育异常，神经内分泌 GnRH 细胞向基底前脑的胚胎迁移缺陷，导致成年后生育能力下降。我们的发现强调了 AMH 在 GnRH 神经元发育和功能中的新作用，并表明 AMH 信号不足导致了人类 CHH 的发病机制。
