ESPE Abstracts (2015) 84 FC14.1

KLB, Encoding the Co-receptor for FGF21, is Mutated in Congenital Hypogonadotropic Hypogonadism

Cheng Xua, Hichem Miraouia, Emmanuel Somma, Tarja Kinnunenb, Andrew Dwyera, Nadia Preitnera, Gerasimos Sykiotisa, Sara Santinia, Richard Quintonc, Lacey Plummerd, William Crowleyd, Michael Hauschilda, Franziska Phan-Huga, Yisrael Sidisa, Moosa Mohammadie, Andrea Messinaa & Nelly Pittelouda


aCentre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; bDepartment of Biology, University of Huddersfield, Huddersfield, UK; cInstitute for Genetic Medicine, University of Newcastle-on-Tyne, Newcastle-on-Tyne, UK; dMassachusetts General Hospital, Boston, Massachusetts, USA; eNew York University School of Medicine, New York, New York, USA


Background: The hepatokine FGF21 signals through a dual receptor complex consisting of FGFR1c and the obligatory co-receptor β-Klotho to regulate glucose and lipid metabolism. Interestingly, female mice with Fgf21 transgenic overexpression are not only resistant to high-fat diet induced obesity but also present with hypogonadotropic hypogonadism (HH) and infertility. Loss-of-function (LOF) mutations in FGFR1 are a frequent cause of congenital HH (CHH). We previously reported a CHH patient with obesity and severe insulin-resistance who harboured a FGFR1 L342S mutation. In vitro studies showed this mutation impaired association of β-Klotho with FGFR1c thereby diminishing FGF21 signalling through FGFR1c.

Objective and hypotheses: We thus hypothesised that mutations in FGF21 and KLB, which encodes β-Klotho, could also underlie CHH.

Method: We screened 295 CHH patients for mutations in FGF21 and KLB. The functionality of the mutants was assessed in vitro using cell-based reporter gene assays, expression studies, and in vivo assays in C. elegans. The reproductive phenotypes of Klb−/− mice were also evaluated.

Results: No mutations were identified in FGF21. We identified nine heterozygous KLB mutations among 13/295 unrelated CHH patients (4%). Five patients harboured the identical KLB deletion (p.Phe777del). The other eight mutations were missense. All mutations have a minor allele frequency (MAF) <1% in the EVS and ExAC databases. All KLB mutants were loss-of-function in vitro and/or in vivo. Additional CHH gene defects were identified in 5/13 patients including two heterozygous FGFR1 mutations, consistent with an oligogenic model of inheritance. Notably, 9/13 subjects also exhibited metabolic defects, such as overweight/obesity, impaired fasting glucose, and/or severe dyslipidaemia. Finally, Klb−/− mice exhibited pubertal delay and decreased fertility.

Conclusion: FGF21/KLB/FGFR1 signalling is implicated in GnRH neuron biology as indicated by LOF KLB mutations in CHH and delayed puberty and infertility in Klb−/− mice.

Funding: This work was supported by the SNF Sinergia (141960).