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Title: KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.
Authors: Xu, Cheng
Messina, Andrea
Somm, Emmanuel
Miraoui, Hichem
Kinnunen, Tarja
Acierno, James
Niederländer, Nicolas J
Bouilly, Justine
Dwyer, Andrew A
Sidis, Yisrael
Cassatella, Daniele
Sykiotis, Gerasimos P
Quinton, Richard
De Geyter, Christian
Dirlewanger, Mirjam
Schwitzgebel, Valérie
Cole, Trevor R
Toogood, Andrew A
Kirk, Jeremy Mw
Plummer, Lacey
Albrecht, Urs
Crowley, William F
Mohammadi, Moosa
Tena-Sempere, Manuel
Prevot, Vincent
Pitteloud, Nelly
Keywords: beta‐klotho;congenital hypogonadotropic hypogonadism;fibroblast growth factor 21;fibroblast growth factor receptor 1
metadata.dc.subject.mesh: Animals
COS Cells
Caenorhabditis elegans
Chlorocebus aethiops
Cohort Studies
Fibroblast Growth Factors
Gonadotropin-Releasing Hormone
HEK293 Cells
Kallmann Syndrome
Klotho Proteins
Membrane Proteins
Mice, Inbred C57BL
Mice, Mutant Strains
Receptor, Fibroblast Growth Factor, Type 1
Issue Date: 2017
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.
metadata.dc.identifier.doi: 10.15252/emmm.201607376
Appears in Collections:Producción 2020

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