期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 118, 期 8, 页码 2822-2831出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI34538
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资金
- NCRR NIH HHS [M01-RR-01066, M01 RR001066] Funding Source: Medline
- NICHD NIH HHS [R01 HD042708, R01 HD015788-21, U54HD028138-16, R01 HD42708, R01 HD015788, U54 HD028138] Funding Source: Medline
- NIDCR NIH HHS [R01 DE013686, R01 DE13686-08] Funding Source: Medline
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.
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