ESPE Abstracts (2015) 84 FC14.1

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).

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