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

摘要: Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated deficiency 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 neuron ontogeny. Using candidate gene approach, we 6 missense FGF8 IHH probands variable olfactory phenotypes. These patients exhibited varied degrees including the rare adult-onset form hypogonadism. Four affected all 4 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 FGF8e FGF8f only. The mutant FGF8b ligands decreased biological activity vitro. Furthermore, mice homozygous hypomorphic Fgf8 allele lacked neurons hypothalamus, heterozygous showed substantial decreases number hypothalamic peptide concentration. In conclusion, as implicated both humans demonstrated an exquisite sensitivity development reductions signaling.