PP30-1 Klb, Encoding the Co-Receptor for FGF21, Is Mutated in Congenital GnRH Deficiency

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: PP30-GnRH & Gonadotrope Biology & Signaling
Monday, June 23, 2014: 11:15 AM-11:30 AM
W181 (McCormick Place West Building)

Poster Board MON-0602
Emmanuel Somm1, Cheng Xu1, Hichem Miraoui1, Tarja Kinnunen2, Nadia Preitner1, Andrew Dwyer, RN, FNP1, Gerasimos Sykiotis1, Richard Quinton3, William F Crowley Jr., MD4, Michael Hauschild1, Franziska Phan-Hug1, Yisrael Sidis1, Moosa Mohammadi5 and Nelly Pitteloud, MD1
1Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 2University of Huddersfield, Huddersfield, United Kingdom, 3University of Newcastle-on-Tyne, Newcastle Upon Tyne, United Kingdom, 4Massachusetts General Hospital, Boston, MA, 5New York University School of Medicine, New York, NY
Background: Loss-of-function (LOF) mutations in FGFR1 are a frequent cause of congenital hypogonadotropic hypogonadism (CHH), a severe form of gonadotropin-releasing hormone (GnRH) deficiency, in males and females. They also predispose females to hypothalamic amenorrhea (HA), a milder and reversible form of GnRH deficiency associated with stress and/or energy deficits. FGF21 is an important metabolic regulator, which signals through a complex of FGFR1c with its co-receptor ß-Klotho. Several lines of evidence support the hypothesis that mutations in KLB, which encodes ß-Klotho, could also underlie CHH by compromising FGF21 signalling: 1) female Fgf21 transgenic (Tg) mice are resistant to high-fat diet and exhibit HH and infertility; 2) a CHH patient, obese with severe insulin-resistance carries a FGFR1 L342S mutation (1) that impairs FGF21 signalling in vitro.

Methods: We screened 295 CHH patients for mutations in KLB and FGF21. The functionality of identified mutations were evaluated in vitro using cell-based reporter gene assays and expression assays, as well as in vivo using rescue experiments in C.elegans deficient of both worm KLB homologues. Klb deficient mice (Klb-/-) were evaluated for reproductive and metabolic phenotypes.

Results: No mutations were identified in FGF21. We identified 9 heterozygous KLB mutations among 13/295 unrelated CHH patients (4%, 9 males and 4 females).  Five patients harbor an identical KLB deletion (p.Phe777del) while the other mutations are missense. All mutations have a MAF<1% in EVS and 1000 genome database and are LOF in vitro and/or in vivo. Additional gene defects in CHH-associated genes were identified in 6/13 patients; these including 3 heterozygous FGFR1 mutations, consistent with an oligogenic model of inheritance. Notably, 10/13 subjects also exhibited metabolic defects, such as obesity, impaired fasting glucose, and/or severe dyslipidemia. Klb-/- mice are smaller in size than wild-type littermates. Female Klb-/- exhibit delayed sexual maturation and irregular estrous cycles, with reduced  time spent in estrous. Further reproductive and metabolic phenotyping of the Klb-/-mice is underway.

Conclusion: Loss-of-function KLB mutations underlie congenital GnRH deficiency. The delayed puberty phenotype of Klb-/- mice supports a role for KLB in reproduction. These findings highlight FGF21 as a probable important link between metabolism and reproduction.

1.  Pitteloud N. et al., J Clin Invest. 2007 Feb;117(2):457-63.

Nothing to Disclose: ES, CX, HM, TK, NP, AD, GS, RQ, WFC Jr., MH, FP, YS, MM, NP

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting

Sources of Research Support: National Institutes of Health R01HD056264 (NP); the Swiss National Science Foundation (NP); FNS-Synergia 141960 (NP)
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