Open AccessKLB , encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism
Author(s) -
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,
TenaSempere Manuel,
Prevot Vincent,
Pitteloud Nelly
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607376
Subject(s) - fgf21 , hypogonadotropic hypogonadism , fibroblast growth factor receptor 1 , endocrinology , medicine , biology , kallmann syndrome , delayed puberty , fibroblast growth factor , genetics , receptor , hormone , disease , covid-19 , infectious disease (medical specialty)
Congenital hypogonadotropic hypogonadism ( CHH ) is a rare genetic form of isolated gonadotropin‐releasing hormone (Gn RH ) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 ( FGFR 1 ) is the most frequently mutated gene in CHH and is implicated in Gn RH neuron development and maintenance. We note that a CHH FGFR 1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF 21 by impairing the association of FGFR 1 with β‐Klotho ( KLB ), the obligate co‐receptor for FGF 21. We thus hypothesized that the metabolic FGF 21/ KLB / FGFR 1 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 Gn RH neurons to release Gn RH in response to FGF 21. Peripheral FGF 21 administration could indeed reach Gn RH neurons through circumventricular organs in the hypothalamus. We conclude that FGF 21/ KLB / FGFR 1 signaling plays an essential role in Gn RH biology, potentially linking metabolism with reproduction.