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

Détails

Ressource 1Télécharger: emmm.201607376.full.pdf (2472.20 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_569EB14591C9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.
Périodique
EMBO molecular medicine
Auteur(s)
Xu C., Messina A., Somm E., Miraoui H., Kinnunen T., Acierno J., Niederländer N.J., Bouilly J., Dwyer A.A., Sidis Y., Cassatella D., Sykiotis G.P., Quinton R., De Geyter C., Dirlewanger M., Schwitzgebel V., Cole T.R., Toogood A.A., Kirk J.M., Plummer L., Albrecht U., Crowley W.F., Mohammadi M., Tena-Sempere M., Prevot V., Pitteloud N.
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Statut éditorial
Publié
Date de publication
10/2017
Peer-reviewed
Oui
Volume
9
Numéro
10
Pages
1379-1397
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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 ( <i>FGFR1</i> ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH <i>FGFR1</i> 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 <i>KLB</i> mutations in 13 patients (4%). Most patients with <i>KLB</i> mutations (9/13) exhibited metabolic defects. In mice, lack of <i>Klb</i> 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.
Mots-clé
Animals, COS Cells, Caenorhabditis elegans/genetics, Cercopithecus aethiops, Cohort Studies, Female, Fibroblast Growth Factors/genetics, Fibroblast Growth Factors/metabolism, Gonadotropin-Releasing Hormone/genetics, Gonadotropin-Releasing Hormone/metabolism, HEK293 Cells, Humans, Hypothalamus/metabolism, Kallmann Syndrome/genetics, Male, Membrane Proteins/genetics, Mice, Inbred C57BL, Mice, Mutant Strains, Neurons/metabolism, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptor, Fibroblast Growth Factor, Type 1/metabolism, beta‐klotho, congenital hypogonadotropic hypogonadism, fibroblast growth factor 21, fibroblast growth factor receptor 1
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/08/2017 12:33
Dernière modification de la notice
20/08/2019 15:10
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