KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

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Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder of sexual maturation characterized by gonadotropin (Gn) deficiency or insensitivity, mainly associated with anomalies in the regulation of GnRH (Gonadotropin Releasing Hormone) signaling and secretion. Impaired GnRH functions lead to major metabolic dysfunctions, reduced or absent puberty, and ultimately infertility.GnRH is a hormone synthesized and released from GnRH neurons within the hypothalamus. Defects in GNRH biology, leading to CHH, need to be explained by identifying the molecular entities involved.By using a set of in-vitro techniques, including Western-blot co-immunoprecipitation and reporter gene assays, Cheng Xu identified the FGFR1/KLB complex as the key element. Site-directed KLB (b-Klotho) mutants displayed impaired functions in-vitro and were correlated with KLB mutations found in humans, by in-depth genotypic and phenotypic clinical studies.Molecular functions of the FGFR1/KLB complex was further confirmed in-vivo by using Caenorhabditis elegans models as well as KLB-deficient knock-out mice.FGFR1/KLB signaling is triggered by the FGF21 ligand. This was illustrated nicely in imaging studies of hypothalamic neurons from mice injected with fluorescently labeled rFGF21.In-vitro, in-vivo, human genetics, and animal models: it’s there to help you fully understand the role of FGF21/FGFR1/KLB signaling in GnRH biology and its impact on human metabolism and reproduction when impaired.


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 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 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 KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb 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.


EMBO Molecular Medicine. 2017 Oct;9(10):1379-1397.

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