Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
Department of Biology, School of Applied Sciences, University of Huddersfield, Huddersfield, UK.
EMBO Mol Med. 2017 Oct;9(10):1379-1397. doi: 10.15252/emmm.201607376.
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 () is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function mutations in 13 patients (4%). Most patients with mutations (9/13) exhibited metabolic defects. In mice, lack of led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
先天性低促性腺激素性性腺功能减退症（CHH）是一种罕见的遗传性单纯促性腺激素释放激素（GnRH）缺乏症，由>30 个基因的突变引起。成纤维细胞生长因子受体 1（）是 CHH 中突变最频繁的基因，与 GnRH 神经元的发育和维持有关。我们注意到，CHH 突变（p.L342S）通过损害 FGFR1 与 FGF21 的必需共受体β-Klotho（KLB）的关联，降低了代谢调节剂 FGF21 的信号转导。因此，我们假设代谢 FGF21/KLB/FGFR1 途径参与 CHH。对 334 名 CHH 患者进行遗传筛查，在 13 名患者（4%）中发现了 7 种杂合失活突变。大多数携带 突变的患者（9/13）表现出代谢缺陷。在小鼠中，缺乏导致青春期延迟、动情周期改变和生育力下降，这是由于下丘脑缺陷导致 GnRH 神经元无法对 FGF21 释放 GnRH。外周 FGF21 给药确实可以通过下丘脑的室周器官到达 GnRH 神经元。我们得出结论，FGF21/KLB/FGFR1 信号转导在 GnRH 生物学中发挥着重要作用，可能将代谢与生殖联系起来。
