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

Cheng Xu, Andrea Messina, Emmanuel Somm, Hichem Miraoui, Tarja Kinnunen, James Acierno, Nicolas J Niederländer, Justine Bouilly, Andrew A Dwyer, Yisrael Sidis, Daniele Cassatella, Gerasimos P Sykiotis, Richard Quinton, Christian De Geyter, Mirjam Dirlewanger, Valérie Schwitzgebel, Trevor R Cole, Andrew A Toogood, Jeremy Mw Kirk, Lacey PlummerUrs Albrecht, William F Crowley, Moosa Mohammadi, Manuel Tena‐sempere, Vincent Prevot, Nelly Pitteloud

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1379-1397
Number of pages9
JournalEMBO Molecular Medicine
Volume9
Issue number10
Early online date28 Jul 2017
DOIs
Publication statusPublished - 1 Aug 2017

Fingerprint Dive into the research topics of 'KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism'. Together they form a unique fingerprint.

  • Cite this