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EMBO Mol Med. 2017 Oct;9(10):1379-1397. doi: 10.15252/emmm.201607376.

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

Author information

1
Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
2
Department of Biology, School of Applied Sciences, University of Huddersfield, Huddersfield, UK.
3
University of Lausanne Institute of Higher Education and Research in Healthcare, Lausanne, Switzerland.
4
Institute for Genetic Medicine, University of Newcastle-on-Tyne, Newcastle-on Tyne, UK.
5
Clinic of Gynecological Endocrinology and Reproductive Medicine, University Hospital, University of Basel, Basel, Switzerland.
6
Pediatric Endocrine and Diabetes Unit, Children's Hospital, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
7
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.
8
Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK.
9
Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK.
10
National Center for Translational Research in Reproduction and Infertility, Harvard Reproductive Endocrine Sciences Center of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
11
Department of Biology, Biochemistry, Faculty of Science, University of Fribourg, Fribourg, Switzerland.
12
Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
13
Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.
14
Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain.
15
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.
16
Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, JPARC, Lille, France.
17
FHU 1000 Days for Health, School of Medicine, University of Lille, Lille, France.
18
Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland nelly.pitteloud@chuv.ch.

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.

KEYWORDS:

beta‐klotho; congenital hypogonadotropic hypogonadism; fibroblast growth factor 21; fibroblast growth factor receptor 1

PMID:
28754744
PMCID:
PMC5623842
DOI:
10.15252/emmm.201607376
[Indexed for MEDLINE]
Free PMC Article

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