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

Cheng Xu1, Andrea Messina1, Emmanuel Somm1

  • 1Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland.

EMBO Molecular Medicine
|July 30, 2017
PubMed

Insights

Genetic mutations in the FGF21/KLB/FGFR1 pathway cause hypogonadotropic hypogonadism, a reproductive disorder. This pathway links metabolism and reproduction by regulating gonadotropin-releasing hormone (GnRH) neuron function.

Area of Science:

  • Endocrinology
  • Reproductive Biology
  • Genetics

Background:

  • Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by isolated gonadotropin-releasing hormone (GnRH) deficiency.
  • Mutations in Fibroblast growth factor receptor 1 (FGFR1) are a common cause of CHH, affecting GnRH neuron development.
  • A specific FGFR1 mutation (p.L342S) impairs FGF21 signaling by disrupting the FGFR1-KLB co-receptor interaction.

Purpose of the Study:

  • To investigate the role of the metabolic FGF21/KLB/FGFR1 pathway in CHH.
  • To identify genetic mutations in KLB associated with CHH in patients.

Main Methods:

  • Genetic screening of 334 CHH patients for KLB mutations.
  • Phenotypic analysis of patients with KLB mutations, including assessment of metabolic defects.
  • Generation and analysis of Klb-deficient mice to study hypothalamic GnRH neuron function and reproductive parameters.
  • Investigation of FGF21 access to GnRH neurons in mice.

Main Results:

  • Seven heterozygous loss-of-function KLB mutations were identified in 13 CHH patients (4%).
  • Nine out of 13 patients with KLB mutations presented with metabolic defects.
  • Klb-deficient mice exhibited delayed puberty, irregular estrous cycles, and subfertility due to impaired GnRH neuron response to FGF21.
  • FGF21 can reach hypothalamic GnRH neurons via circumventricular organs.

Conclusions:

  • The FGF21/KLB/FGFR1 signaling pathway is crucial for GnRH biology and reproductive function.
  • This pathway represents a potential link between metabolic regulation and reproduction.
  • KLB mutations are a novel genetic cause of CHH, often associated with metabolic abnormalities.

Keywords:
beta‐klothocongenital hypogonadotropic hypogonadismfibroblast growth factor 21fibroblast growth factor receptor 1

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