Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
John Falardeau, … , Pei Tsai, Nelly Pitteloud
John Falardeau, … , Pei Tsai, Nelly Pitteloud
Published July 1, 2008
Citation Information: J Clin Invest. 2008;118(8):2822-2831. https://doi.org/10.1172/JCI34538.
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Research Article Reproductive biology

Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adult-onset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling.

Authors

John Falardeau, Wilson C.J. Chung, Andrew Beenken, Taneli Raivio, Lacey Plummer, Yisrael Sidis, Elka E. Jacobson-Dickman, Anna V. Eliseenkova, Jinghong Ma, Andrew Dwyer, Richard Quinton, Sandra Na, Janet E. Hall, Celine Huot, Natalie Alois, Simon H.S. Pearce, Lindsay W. Cole, Virginia Hughes, Moosa Mohammadi, Pei Tsai, Nelly Pitteloud

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Figure 4

Structural modeling of K71E and R98G FGF8 mutations predicts that they are loss-of-function mutations.

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Structural modeling of K71E and R98G FGF8 mutations predicts that they a...
The locations of the mutated FGF8 residues are mapped onto the ribbon diagram of 2:2:2 FGF8b/FGFR2c/heparin complex. Orange and purple denote the core and N terminus, respectively, of FGF8b. Green, cyan, and gray denote D2, D3, and D2-D3 linker, respectively, of the extracellular FGFR2c ligand-binding region. The 2 heparin oligosaccharides are rendered as blue sticks and surface representations. Also shown are detailed views of the regions where the mutated FGF8 residues are located. Selected residues are shown as ball-and-stick representations, as is F32 of FGF8b N terminus to underscore the importance of the FGF8b N terminus in FGF8b-FGFR binding. Blue balls, nitrogen atoms; red balls, oxygen atoms. Hydrogen bonds are shown as dashed lines. The N and C termini of polypeptide chains are indicated.