Skip to Main content Skip to Navigation
Journal articles

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

Abstract : 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.
Document type :
Journal articles
Complete list of metadata

https://www.hal.inserm.fr/inserm-03204366
Contributor : Vincent Prevot Connect in order to contact the contributor
Submitted on : Wednesday, April 21, 2021 - 2:24:58 PM
Last modification on : Tuesday, October 19, 2021 - 10:56:58 PM
Long-term archiving on: : Thursday, July 22, 2021 - 6:46:05 PM

File

emmm.201607376.pdf
Publication funded by an institution

Identifiers

Collections

Citation

Cheng Xu, Andrea Messina, Emmanuel Somm, Hichem Miraoui, Tarja Kinnunen, et al.. KLB , encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO Molecular Medicine, Wiley Open Access, 2017, 9 (10), pp.1379-1397. ⟨10.15252/emmm.201607376⟩. ⟨inserm-03204366⟩

Share

Metrics

Record views

14

Files downloads

33