RT Journal Article
T1 KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.
A1 Xu, Cheng
A1 Messina, Andrea
A1 Somm, Emmanuel
A1 Miraoui, Hichem
A1 Kinnunen, Tarja
A1 Acierno, James
A1 Niederländer, Nicolas J
A1 Bouilly, Justine
A1 Dwyer, Andrew A
A1 Sidis, Yisrael
A1 Cassatella, Daniele
A1 Sykiotis, Gerasimos P
A1 Quinton, Richard
A1 De Geyter, Christian
A1 Dirlewanger, Mirjam
A1 Schwitzgebel, Valérie
A1 Cole, Trevor R
A1 Toogood, Andrew A
A1 Kirk, Jeremy Mw
A1 Plummer, Lacey
A1 Albrecht, Urs
A1 Crowley, William F
A1 Mohammadi, Moosa
A1 Tena-Sempere, Manuel
A1 Prevot, Vincent
A1 Pitteloud, Nelly
K1 Beta‐klotho
K1 Congenital hypogonadotropic hypogonadism
K1 Fibroblast growth factor 21
K1 Fibroblast growth factor receptor 1
AB 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.
PB EMBO Press
YR 2017
FD 2017-06-27
LK http://hdl.handle.net/10668/11454
UL http://hdl.handle.net/10668/11454
LA en
NO Xu C, Messina A, Somm E, Miraoui H, Kinnunen T, Acierno J Jr, et al. KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO Mol Med. 2017 Oct;9(10):1379-1397
NO This work was supported by the Swiss National Science Foundation Sinergia Grant (CRSII3_141960, N. Pitteloud, U. Albrecht and M. Mohammadi); the Swiss National Science Foundation grant (SNF 31003A 153328, N. Pitteloud); the Agence National pour la Recherche (ANR, France) Grant GlioShuttles4Metabolism (ANR-15-CE14-0025, V. Prévot); the grant BFU2014-57581-P (Ministerio de Economía y Competitividad, Spain; co-funded with EU funds from FEDER Program, M. Tena-Sempere);the National Institute of Dental and Craniofacial Research at the NationalInstitutes of Health Grant (R01 DE-13686 to M. Mohammadi); the HarvardReproductive Endocrine Sciences Center of Excellence in TranslationalResearch in Reproduction & Infertility: The Eunice Shriver NationalInstitute of Child Health and Human Development (NICHD P50 HD-28138,W. Crowley).
DS RISalud
RD Apr 18, 2025